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A novel dendritic cell subset involved in tumor immunosurveillance
Abstract
The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.
... Studies using murine models have identified a rare chimeric cell population called interferon (IFN)-producing killer dendritic cells (IKDCs), exhibiting both NK and DC activities. IKDCs can kill tumors, function as APCs by capturing apoptotic tumor cells [6][7][8], and target and eliminate tumors while cross-presenting tumor antigens to prime CD8 T cells with tumor specificity [9]. In other words, they can exert innate killer cell cytotoxicity and present tumor antigens, bridging adaptive CD8 T-cell immune responses against tumors. ...
... Phyduxon exhibited NK-dependent killing activity and APC function, while the TAA-specific CD8 T cells were responsible for T cell-dependent cytotoxicity toward OC cells (Fig. 6). Mouse IKDC was first discovered in 2006 and defined as NK1.1 + B220 + CD11c int [7,8]. Mouse IKDCs secrete IFN-γ and mediate tumoricidal activity in a TRAILdependent manner [8] and also secrete IL-12 to upregulate the expression of MHC-II and costimulatory molecules, thereby acquiring APC function [7,29]. ...
... Mouse IKDC was first discovered in 2006 and defined as NK1.1 + B220 + CD11c int [7,8]. Mouse IKDCs secrete IFN-γ and mediate tumoricidal activity in a TRAILdependent manner [8] and also secrete IL-12 to upregulate the expression of MHC-II and costimulatory molecules, thereby acquiring APC function [7,29]. Adoptively transferring this particular immune subset, exhibiting the phenotype and properties of both NK cells and DCs, results in antitumor activity in vivo [9]. ...
Background
Although immune cell therapy has long been used for treating solid cancer, its efficacy remains limited. Interferon (IFN)-producing killer dendritic cells (IKDCs) exhibit cytotoxicity and present antigens to relevant cells; thus, they can selectively induce tumor-associated antigen (TAA)-specific CD8 T cells and may be useful in cancer treatment. Various protocols have been used to amplify human IKDCs from peripheral sources, but the complexity of the process has prevented their widespread clinical application. Additionally, the induction of TAA-specific CD8 T cells through the adoptive transfer of IKDCs to immunocompromised patients with cancer may be insufficient. Therefore, we developed a method for generating an immune cell-based regimen, Phyduxon-T, comprising a human IKDC counterpart (Phyduxon) and expanded TAA-specific CD8 T cells.
Methods
Peripheral blood mononuclear cells from ovarian cancer patients were cultured with human interleukin (hIL)-15, hIL-12, and hIL-18 to generate Phyduxon-T. Then, its phenotype, cytotoxicity, and antigen-presenting function were evaluated through flow cytometry using specific monoclonal antibodies.
Results
Phyduxon exhibited the characteristics of both natural killer and dendritic cells. This regimen also exhibited cytotoxicity against primary ovarian cancer cells and presented TAAs, thereby inducing TAA-specific CD8 T cells, as evidenced by the expression of 4-1BB and IFN-γ. Notably, the Phyduxon-T manufacturing protocol effectively expanded IFN-γ-producing 4-1BB⁺ TAA-specific CD8 T cells from peripheral sources; these cells exhibited cytotoxic activities against ovarian cancer cells.
Conclusions
Phyduxon-T, which is a combination of natural killer cells, dendritic cells, and TAA-specific CD8 T cells, may enhance the efficacy of cancer immunotherapy.
... Interestingly, it was suggested that CD40-ligation [77] or the action of regulatory T cells (Tregs) [94] could inhibit the upregulation of TRAIL on stimulated human DCs. Similar to humans, in mice, TRAIL was found to be upregulated on mouse DCs by IFNα and IFNβ directly [86] or indirectly [94][95][96]. Furthermore, IL-15 was suggested to be an inducer of TRAIL expression on mouse DCs [97,98]. ...
... This was reported for unstimulated DCs [46,102], for IFNα/β stimulated monocyte-derived DCs [49,77,[81][82][83]87,92,103,104], for pDCs [78,79], and for DCs stimulated with TLR-ligands [77,84,88] or virus particles [85,88,91,93,105]. Similar observations were made in the mouse system [86,95,96,98]. Interestingly, two studies suggest that TRAIL/DR interaction can also have a direct impact on the TRAIL + DCs in an apoptosis-independent manner, although, they conflict in their implication. ...
... Many immune cells express TRAIL constitutively or following activation and thereby can be cytotoxic to TRAIL-sensitive tumor cells in vitro and in vivo. This has been reported for neutrophils [13,14,17,42,43], monocytes/macrophages [17,47,52,73], DCs [46,49,[77][78][79][81][82][83]86,87,91,98,[102][103][104], pDCs [84,85,88,91,93,95,96,105], cNK/ILC1s [134,136,137,163,228,282], iNKT cells [218,219,225,227,229], γδ T cells [231,235], and conventional T cells [186,194,[283][284][285][286]. ...
Expression of TRAIL (tumor necrosis factor–related apoptosis–inducing ligand) by immune cells can lead to the induction of apoptosis in tumor cells. However, it becomes increasingly clear that the interaction of TRAIL and its death receptors (DRs) can also directly impact immune cells and influence immune responses. Here, we review what is known about the role of TRAIL/DRs in immune cells and immune responses in general and in the tumor microenvironment in particular.
... Pre-mNK cells are phenotypically defined as B220 + CD11c + MHC class II (MHC-II) + NK1.1 + cells and comprise an intermediate in the differentiation pathway of conventional NK cells. They were initially called IFN-producing killer DCs (IKDCs), due ostensibly to their versatility in migrating to lymph nodes to present Ags, in synthesizing copious amounts of IL-12, type I IFN, and IFN-g, and in exerting tumoricidal activities (23,24). Subsequently, IKDCs were reported to belong to the NK lineage as evidenced by their strict developmental dependence on IL-15 (25)(26)(27) and their propensity to acquire an mNK cell phenotype upon adoptive transfer (28). ...
... We found them to also express B220 and NK1.1 (Fig. 1A), which are usually considered B cell/plasmacytoid DCs and NK cell markers, respectively. The only cell type that concomitantly expresses CD11c, B220, and NK1.1 is the pre-mNK cell (23,24) whose tissue presence has been reported in the bone marrow, spleen, and lymph nodes (23,24,26,34,35) but never in the liver before. ...
... We found them to also express B220 and NK1.1 (Fig. 1A), which are usually considered B cell/plasmacytoid DCs and NK cell markers, respectively. The only cell type that concomitantly expresses CD11c, B220, and NK1.1 is the pre-mNK cell (23,24) whose tissue presence has been reported in the bone marrow, spleen, and lymph nodes (23,24,26,34,35) but never in the liver before. ...
Invariant NKT (iNKT) cells are innate-like T lymphocytes that recognize and respond to glycolipid Ags such as α-galactosylceramide (α-GalCer). This unique property has been exploited in clinical trials for multiple malignancies. While investigating mouse iNKT cell responses to α-GalCer in vivo, we found a dramatically enlarged tissue-resident population surprisingly coexpressing select dendritic cell, NK cell, and B cell markers. Further phenotypic and functional analyses revealed the identity of this B220+CD11c+MHC class II+NK1.1+ population as precursors to mature NK (pre-mNK) cells, which also expressed high levels of proliferation and tissue retention markers but diminished sphingosine-1-phosphate receptor 1, a receptor that facilitates tissue trafficking. Accordingly, FTY720, a sphingosine-1-phosphate receptor 1 antagonist, failed to prevent pre-mNK cells' intrahepatic accumulation. We found iNKT cell-driven expansion of pre-mNK cells to be dependent on IL-12 and IL-18. Although α-GalCer-transactivated pre-mNK cells lost their capacity to process a model tumor Ag, they selectively expressed granzyme A and directly lysed YAC-1 thymoma cells through granule exocytosis. They also contributed to β2 microglobulin-deficient target cell destruction in vivo. Therefore, α-GalCer treatment skewed pre-mNK cell responses away from an APC-like phenotype and toward killer cell-like functions. Finally, the ability of α-GalCer to reduce the pulmonary metastatic burden of B16-F10 mouse melanoma was partially reversed by in vivo depletion of pre-mNK cells. To our knowledge, our findings shed new light on iNKT cells' mechanism of action and glycolipid-based immunotherapies. Therefore, we introduce pre-mNK cells as a novel downstream effector cell type whose anticancer properties may have been overlooked in previous investigations.
... Pre-mNK cells are phenotypically defined as B220 + CD11c + MHC class II (MHC-II) + NK1.1 + cells and comprise an intermediate in the differentiation pathway of conventional NK cells. They were initially called IFN-producing killer DCs (IKDCs), due ostensibly to their versatility in migrating to lymph nodes to present Ags, in synthesizing copious amounts of IL-12, type I IFN, and IFN-g, and in exerting tumoricidal activities (23,24). Subsequently, IKDCs were reported to belong to the NK lineage as evidenced by their strict developmental dependence on IL-15 (25)(26)(27) and their propensity to acquire an mNK cell phenotype upon adoptive transfer (28). ...
... We found them to also express B220 and NK1.1 (Fig. 1A), which are usually considered B cell/plasmacytoid DCs and NK cell markers, respectively. The only cell type that concomitantly expresses CD11c, B220, and NK1.1 is the pre-mNK cell (23,24) whose tissue presence has been reported in the bone marrow, spleen, and lymph nodes (23,24,26,34,35) but never in the liver before. ...
... We found them to also express B220 and NK1.1 (Fig. 1A), which are usually considered B cell/plasmacytoid DCs and NK cell markers, respectively. The only cell type that concomitantly expresses CD11c, B220, and NK1.1 is the pre-mNK cell (23,24) whose tissue presence has been reported in the bone marrow, spleen, and lymph nodes (23,24,26,34,35) but never in the liver before. ...
Stress is known to impede certain host defense mechanisms, including those governed by conventional T lymphocytes. However, whether innate-like T lymphocytes, such as invariant natural killer T (iNKT)and mucosa-associated invariant T (MAIT)cells, are impacted by stress is unclear. Herein, we report that prolonged psychological stress caused by physical confinement results in robust upregulation of T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), an immune checkpoint receptor that controls antitumor and antiviral immune responses. Elevated TIGIT expression was found not only on NK and conventional T cells, but also on iNKT and MAIT cells. Stress-provoked TIGIT upregulation was reversed through treatment with the glucocorticoid receptor (GR)antagonist RU486, but not with 6-hydroxydopamine that induces chemical sympathectomy. A Cre/Lox gene targeting model in which GR was ablated in cells expressing Lck under its proximal promoter revealed that TIGIT upregulation in stressed animals stems from direct GR signaling in T and iNKT cells. In fact, long-term oral administration of exogenous corticosterone (CS)to wild-type C57BL/6 (B6)mice was sufficient to increase TIGIT expression levels on T and iNKT cells. In vitro treatment with CS also potently and selectively upregulated TIGIT, but not CTLA-4 or LAG-3, on mouse iNKT and MAIT hybridomas. These results were recapitulated using primary hepatic iNKT and MAIT cells from wild-type B6 and B6.MAITCAST mice, respectively. Subjecting B6.MAITCAST mice to physical restraint also raised the frequency of TIGIT⁺ cells among hepatic MAIT cells in a GR-dependent manner. Finally, we found that TIGIT is similarly upregulated in a chronic variable stress model in which animals are exposed to unpredictable heterotypic stressors without developing habituation. Taken together, our findings link, for the first time to our knowledge, GR signaling to TIGIT expression. We propose that glucocorticoid hormones dampen immune responses, in part, by enhancing TIGIT expression across multiple critical subsets of effector lymphocytes, including innate-like T cells. Therefore, TIGIT may constitute an attractive target in immune-enhancing interventions for sustained physiological stress.
... Some of these cells include the IKDCs which participate in the induction and the regulation of immunity and constitute a link between innate and adaptive immune response [14,15]. These subsets play a role in tumor growth through the production of IFN-γ [16][17][18][19]. The IKDCs also possess properties of both NKs and DCs as cytotoxic functions and antigen presentation. ...
... They are defined by the expression of several molecular markers such as: B220 + CD11c + CD49b + CD86 + CD122 + NK1.1 + and MHC-II + [20,21]. The distribution of IKDCs is along the lymphoid organs of several mice strains that include C57BL/6J [16,22]. Recently, there was a report indicating the involvement of IKDCs in the control of autoimmune diseases and inflammatory responses [23,24]. ...
... NK-like cells are elevated in lupus-prone mice models [11,12]. One of these NK-like cells, the recently described interferonproducing killer dendritic cells, is reported as having a role in controlling autoimmune diseases [16,17,23,24]. Our group previously found a B220 + CD38 + CD24 − CD21 − population; recent information from the literature suggested us that it may correspond to IKDC lymphocytes [25]. ...
A novel cell population denominated IFN‐γ‐producing killer dendritic cells (IKDCs), has been recently described. These cells are lymphocytes lacking B‐ or T‐ receptors, but they can be identified by the presence of B220⁺ CD38⁺ CD49b⁺ and low CD11c, among other cell surface markers. The main characteristics of IKDCs are the production of IFN‐γ and the ability to spontaneously kill tumor cells. We found that this population increases in B6.MLR‐Faslpr/J mice. Interestingly, IKDCs increase with age and are more abundant in mice older than six months onwards. To analyze whether these cells have any role in the induction of the lupus‐like phenotype in the B6.MLR‐Faslpr/J mice, IKDCs were purified and transferred into 6‐months old B6.MRL‐Faslpr/J mice, then the presence of anti‐nuclear antibodies (ANAS) and anti‐dsDNA antibodies were analyzed two and four months after the transfer. The results showed a reduction in the levels of these autoantibodies and increased survival of these mice, indicating that these cells may have a regulatory function. In vitro assays demonstrated that IKDCs reduced the proliferation of both autoreactive B and T cells, suggesting that this may be the mechanisms used by these cells to ameliorate the lupus‐like phenotype in the B6.MRL‐Faslpr/J mice.
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... It is important to note that while total NK cells provide important contributions to the innate effector response of TVQC, in our studies, we observed that the CD11c+ NK subset (NKDC) exhibited a more potent functional phenotype than the CD11c− subset ( Figure 2C), highlighting the significance of NKDCs in antitumor immunity. Similar to our findings, others have reported increased IFNg production by NKDCs compared to total NK cells [33,34]. Here, in addition to elevated IFNg, we show enhanced cytotoxicity shown by granzyme B and higher polyfunctionality (GrnzB+, IFNg+) from TVQC, all of which are known to be key components of the antitumor response [34,35]. ...
... Similar to our findings, others have reported increased IFNg production by NKDCs compared to total NK cells [33,34]. Here, in addition to elevated IFNg, we show enhanced cytotoxicity shown by granzyme B and higher polyfunctionality (GrnzB+, IFNg+) from TVQC, all of which are known to be key components of the antitumor response [34,35]. ...
High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction of a strong cytotoxic T cell response. However, TVAC was insufficient in the clearance of HPV oral tumors. To overcome this deficiency, we tested substituting aGalCer with a clinically relevant adjuvant QS21 (TVQC) and observed sustained, complete regression of over 70% of oral and 80% of vaginal HPV tumors. The TVQC-mediated protection in the oral tumor model correlated with not only strong total and HPV-antigen-specific CD8 T cells, but also natural killer dendritic cells (NKDCs), a novel subset of NK cells expressing the DC marker CD11c. Notably, we observed induction of significantly higher overall innate NK effector responses by TVQC relative to TVAC. Furthermore, in mice treated with TVQC, the frequencies of total and functional CD11c+ NK cell populations were significantly higher than the CD11c− subset, highlighting the importance of the contributions of NKDCs to the vaccine response. These results emphasize the importance of NK-mediated innate immune effector responses in total antitumor immunity to treat HPV+ cancers.
... Both CD95 and INF signatures have been involved in the progression of lupus, but whether a link exists between these two pathways remains to be elucidated. Although the elimination of the INFγR in MRL/Lpr mice (CD95 deficient mice) protected them from glomerulonephritis, it remains inefficient to prevent lymphadenopathy and accumulation of double-negative T-cell (B220+CD3+CD4-CD8-) [122]. Interestingly skin lesions were higher in the INFγR −/− MRL/Lpr mice as compared to their MRL/Lpr counterparts, suggesting a protective role of this signal in the skin inflammation [122]. ...
... Although the elimination of the INFγR in MRL/Lpr mice (CD95 deficient mice) protected them from glomerulonephritis, it remains inefficient to prevent lymphadenopathy and accumulation of double-negative T-cell (B220+CD3+CD4-CD8-) [122]. Interestingly skin lesions were higher in the INFγR −/− MRL/Lpr mice as compared to their MRL/Lpr counterparts, suggesting a protective role of this signal in the skin inflammation [122]. cGAS or STING elimination in different models of lupus, in which CD95/Fas has been involved, also suggests that these factors could protect from the pathology progression. ...
Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take place render it difficult to predict what will be the cellular outcome associated with the receptor engagement. Accordingly, CD95 stimulation can trigger apoptosis, necroptosis, pyroptosis, or pro-inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphatidylinositol-3-kinase (PI3K). Recent data suggest that CD95 can also activate pattern recognition receptors (PRRs) known to sense damage-associated molecular patterns (DAMPs) such as DNA debris and dead cells. This activation might contribute to the pro-inflammatory role of CD95 and favor cancer development or severity of chronic inflammatory and auto-immune disorders. Herein, we discuss some of the molecular links that might connect the CD95 signaling to DAMP sensors.
... In this study, we set out to investigate the cytotoxic diversification of pDCs to a similar extend as observed for IFN-I production. More specifically, we studied whether the small fractions of early IFN-I producers express cytotoxic markers, since so-called IFN-producing killer (p)DCs (IKDC/ IKpDCs) have been described in the past (22)(23)(24)(25)(26)(27). PD-L1 and TNF-related apoptosis-inducing ligand (TRAIL) have been known for their role in pDC cytotoxicity [reviewed in (3,7)], and were therefore, together with a functional IFN-I readout, the main focus of this study. ...
... The combination of IFN-I production and strong cytotoxic or antitumor activities has been described for (p)DCs in numerous studies (22)(23)(24)(25)(26)(27). Therefore, we next zoomed in on the expression of cytotoxic markers on the fraction of early IFN-producing pDCs. ...
Plasmacytoid dendritic cells (pDCs) are a rare type of highly versatile immune cells that besides their specialized function of massive type I interferon (IFN-I) production are able to exert cytotoxic effector functions. However, diversification upon toll like receptor (TLR)-induced activation leads to highly heterogeneous responses that have not been fully characterized yet. Using droplet-based microfluidics, we showed that upon TLR7/8 and TLR9-induced single-cell activation only 1-3% secretes IFNα, and only small fractions upregulate cytotoxicity markers. Interestingly, this 1-3% of early IFN-producing pDCs, also known as first responders, express high levels of programmed death-ligand 1 (PD-L1) and TNF-related apoptosis-inducing ligand (TRAIL), which makes these hybrid cells similar to earlier described IFN-I producing killer pDCs (IKpDCs). IFN-I priming increases the numbers of IFNα producing cells up to 40%, but does not significantly upregulate the cytotoxicity markers. Besides, these so-called second responders do not show a cytotoxic phenotype as potent as observed for the first responders. Overall, our results indicate that the first responders are the key drivers orchestrating population wide IFN-I responses and possess high cytotoxic potential.
... In these earlier studies, many and diverse mechanisms of action were suggested, including immune-specific tolerance through the induction of T-regulatory cells, IL-10 secretion, and IL-2 inhibition 3,9,12,37 ; nonspecific inhibition through the NO system 10,38-40 ; inhibition via indoleamine 2,3-dioxygenase 37,41 ; and apoptosis through death receptors including Fas, TRAIL, and TNF. [13][14][15]17,39,42,43 Likewise, our results suggest that BM-derived DCs obtained after culturing of whole BM with either GM-CSF (supplemental Figure 4) or FLT3 ligand 44 (supplemental Figure 5) do not exhibit detectable levels of perforin or appreciable killing of cognate 2C CD8 T cells. Therefore, our results suggest that the perforin ϩ imDCs grown in our study from purified HSCs represent a novel subpopulation found in a small percentage in the spleen under steady state, which nevertheless can expand in the spleen after GM-CSF administration in vivo. ...
... The possibility that imDCs prepared by our protocol resemble the so-called NKDCs or IKDCs previously reported to exhibit dual NK and DC properties 43,50,51 or activated NK cells 52,53 was negated by the demonstration that they do not express markers typically associated with NK cells, such as NK1.1, DX5, and NKp46, and are negative for B220, which was shown to be expressed by IKDCs. The fact that NKDCs fail to kill T cells, but rather induce T-cell proliferation, 50,51 further rule out this possibility. ...
65
The mechanism underlining tolerance induction by immature myeloid dendritic cells (IMDC) is poorly understood. To address this issue, we generated mouse IMDC from hematopoietic stem cells (HSC) via differentiation to early myeloid cells (10 days with a cytokine cocktail containing: TPO, Flt-3L, SCF, IL-3 and IL-6) and further differentiation to IMDC (10% GM-CSF for an additional 10 days). The phenotype of the cells obtained at the end of this procedure was CD11c+, CD11b+, B220−, CD80+, MHC class II + Low and CD86−.
Addition of the IMDC to long term ( 3 days) mixed lymphocyte reaction (MLR) in which TCR transgenic (Tg) CD4+ or CD8+ alloreactive T cells are reacted against their cognate MHC antigens, led to a marked inhibition of proliferation (reaction ratio 1 IMDC: 2 T cells). This suppression was found to be mediated In short term MLR ( 5 hours) through killing of the effector cells.
Killing of CD4+ alloreactive T cells was found to be MHC independent; namely, IMDC expressing MHC not recognized by the TCR transgene exhibited similar inhibition as that exhibited by IMDC expressing the cognate MHC (55±3% versus 59±4% killing upon addition of cognate MHC or non-cognate MHC IMDC, respectively).
As previously shown, this non-specific killing is likely mediated by the NO system, as it could be completely abrogated by pre-treatment with N (G)-nitro-L- arginine methyl ester (L-NAME ) (5±4% and 4±3% killing upon addition of pre- treated IMDC bearing cognate MHC or non-cognate MHC, respectively).
In contrast, killing of CD8+ alloreactive T cells by IMDC was only slightly reversed by L-NAME (74±3% killing with non-treated IMDC bearing cognate MHC, compared to 68±4% after pre treatment with L-NAME), and the remaining killing activity was found to be MHC dependent. Thus, in contrast to cognate IMDC, very low killing of alloreactive TCR transgenic CD8 T cells was exhibited by non-cognate IMDC in the presence of L-NAME (5±2% killing). When tested in a mouse model of T cell mediated bone marrow (BM) allograft rejection, only IMDC of donor, but not of third party origin, could prolong graft survival upon infusion of 3×106 IMDC (median survival of 24 versus 10 days respectively, p<0.05) suggesting that only the MHC dependent tolerance mechanism is operative in this graft rejection model.
Surprisingly, the MHC dependent killing exhibited by IMDC in short term MLR was completely lost when using IMDC generated from perforin KO mice or when IMDC were pre-treated with Bapta-AM or Concanamycin A (6±4%, 5±3% and 3±3% killing, respectively). Thus, killing of the responding alloreactive CD8+ T cells by their cognate IMDC involves a perforin/granzyme mediated mechanism. Indeed, Electron Microscopy (EM) analysis revealed that IMDC were loaded with granules containing perforin and Granzyme A, mostly localized in proximity to the cell membrane. While these granules could barely be detected in early myeloid cells, formation of granules was markedly enhanced upon differentiating into IMDC.
Further EM analysis revealed that recognition of the IMDC by alloreactive CD8+ T cells induced granules polarization towards the area of contact. Live video imaging (using perforin and granzyme A immunostaining) further supported the suggestion that this granule polarization leads to specific killing of the responding CD8+ T cell. Furthermore, pre-treatment of IMDC with a blocking peptide for Toll like receptor 7 (TLR7) but not for TLR1, TLR5, TLR6, TLR9, TLR10, or TLR11, completely abolished this granule degranulation, and the eventual killing of alloreactive CD8+ T cells (blocking TLR7 reduced the MLR inhibition from 68±4% to 8±3%, p<0.01). Thus, MHC dependent killing of alloreactive CD8+ T cells by IMDC is likely triggered by TCR recognition of the cognate MHC on the IMDC which, in turn, activate Toll receptor signaling leading to degranulation and granule mediated killing.
In conclusion, IMDC can induce immune tolerance through two distinct mechanisms. The first, mediated by the NO system, is MHC independent and is limited to ablation of CD4+ T cell responses. The second, mainly targeting CD8+ T cells, is MHC dependent and is mediated by cytotoxic granules in the IMDC which polarize towards the contact area upon recognition by the T cells. This MHC- specific mechanism is clearly dependent on perforin and is specifically triggered by TLR7 ligation. The latter mechanism was predominant when testing IMDC in a mouse model for T cell mediated BM allograft rejection.
Disclosures
No relevant conflicts of interest to declare.
... Although mouse NK cells do not endogenously express MHC class II molecules, but only acquire them through membrane transfer from DCs (129), in 2006, a mouse-specific immune cell subset displaying Porcine NK cells display features associated with antigen presenting cells -82 -characteristics of both NK cells and DCs, called IFN-producing killer DCs or NK-DCs, was described, (135,136) which is now called pre-mature NK (pre-mNK) cells (137)(138)(139)(140)(141). These pre-mNK cells are able to present antigens to naïve T cells after killing (135,136). The potential pre-mNK analog in humans is the HLA-DR + NK cell (127), which can play a role in inflammatory responses (125). ...
... Although mouse NK cells do not endogenously express MHC class II molecules, but only acquire them through membrane transfer from DCs (129), in 2006, a mouse-specific immune cell subset displaying Porcine NK cells display features associated with antigen presenting cells -82 -characteristics of both NK cells and DCs, called IFN-producing killer DCs or NK-DCs, was described, (135,136) which is now called pre-mature NK (pre-mNK) cells (137)(138)(139)(140)(141). These pre-mNK cells are able to present antigens to naïve T cells after killing (135,136). The potential pre-mNK analog in humans is the HLA-DR + NK cell (127), which can play a role in inflammatory responses (125). ...
... According to their unique pathway for differentiation from bone marrow (37), ability to respond to IL-15 (32), and distinct transcriptional profile from that of NK cells (38), IKDCs seemingly belong to a subpopulation of DCs that differs from NK cells (34). More recently, these IKDCs exhibiting features of both NK cells and DCs (29,31,36) now have been revisited as part of the NK cell lineage and have been renamed as premature NK cells (pre-mNK cells), resulting in an endless lineage debate (36,39,40). ...
... Moreover, B-, T-, and NK cell-associated surface markers were not related to either BMDCs or IL-15-DBMCs (Fig. S4). IKDCs have been reported to be CD11c int B220 + DX5 + (or NK1.1 + ) and Gr-1 - (29,31,34). pDCs, a type of DC, are also known to express intermediate levels of CD11c, and Siglec-H and PDCA-1 have been shown to be specific markers for pDCs (33,72,73). ...
Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-γ-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic characteristics of IFN-γ-producing IL-15-DBMCs and their functional role in the control of intracellular Mycobacterium tuberculosis (Mtb) infection. When comparing the cytokine levels between bone marrow-derived dendritic cells (BMDCs) and IL-15-DBMCs upon stimulation with various TLR agonists, only the CD11cint population of IL-15-DBMCs produced significant levels of IFN-γ, decreased levels of MHC-II, and increased levels of B220. Neither BMDCs nor IL-15-DBMCs were found to express DX5 or NK1.1, which are representative markers for the NK cell lineage and IKDCs. When the CD11cintB220⁺ population of IL-15-DBMCs was enriched, the Thy1.2⁺Sca-1⁺ population showed a marked increase in IFN-γ production. In addition, while depletion of the B220⁺ and Thy1.2⁺ populations of IL-15-DBMCs, but not the CD19⁺ population, inhibited IFN-γ production, enrichment of these cell populations increased IFN-γ. Ultimately, co-culture of sorted IFN-γ-producing B220⁺Thy1.2⁺ IL-15-DBMCs with Mtb-infected macrophages resulted in control of the intracellular growth of Mtb via the IFN-γ-nitric oxide axis in a donor cell number-dependent manner. Taken together, the results indicate that IFN-γ-producing IL-15-DBMCs could be redefined as CD11cintB220⁺Thy1.2⁺Sca-1⁺ cells, which phenotypically resemble both IKDCs and ILC1s, and may have therapeutic potential for controlling infectious intracellular bacteria such as Mtb.
... DCs are generally divided into two major subtypes, myeloid DCs and plasmacytoid DCs (pDCs); however, in mice, interferon-producing killer DCs (IKDCs) have been described as a third subtype 11,12 . These latter cells produce substantial amounts of type I interferon (IFN) and IL-12 or IFN-γ , depending on the activating stimuli and can kill typical targets of natural killer (NK) cells via NK-activating receptors in response to stimulation with CpG 11 . ...
... These latter cells produce substantial amounts of type I interferon (IFN) and IL-12 or IFN-γ , depending on the activating stimuli and can kill typical targets of natural killer (NK) cells via NK-activating receptors in response to stimulation with CpG 11 . In particular, B220 + NK1.1 + DCs have been reported to secrete large amounts of IFN-α and to promote the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent lysis of tumour cells 12 . In addition to IKDCs in mice, several subsets of killer DCs that exhibit anti-tumour cytotoxicity have been reported in humans 13 . ...
Active human dendritic cells (DCs), which efficiently induce immune responses through their functions as antigen-presenting cells, exhibit direct anti-tumour killing activity in response to some pathogens and cytokines. These antigen-presenting and tumour killing abilities may provide a breakthrough in cancer immunotherapy. However, the mechanisms underlying this killer DC activity have not been fully proven, despite the establishment of interferon-α (IFN-α)-generated killer DCs (IFN-DCs). Here mature IFN-DCs (mIFN-DCs), generated from IFN-DCs primed with OK-432 (streptococcal preparation), exhibited elevated expression of CD86 and human leukocyte antigen-DR (minimum criteria for DC vaccine clinical trials) as well as antigen-presenting abilities comparable with those of mature IL-4-DCs (mIL-4-DCs). Interestingly, the killing activity of mIFN-DCs, which correlated with the expression of CD56 (natural killer cell marker) and was activated via the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand pathway, was stronger than that of IFN-DCs and remarkably stronger than that of mIL-4-DCs. Therefore, mIFN-DCs exhibit great potential as an anti-cancer vaccine that would promote both acquired immunity and direct tumour killing.
... Although not specific to this cell type, another study did identify overall inflammatory pathways when looking at the placental epigenetic dysregulation in new onset postpartum preeclampsia (1). We also identified a commonly distinct cluster 3, which had a cytotoxic gene signature resembling previously reported "natural killer dendritic cells", in addition to co-expressing known classical monocyte genes suggesting a common role in the postpartum period (34)(35)(36). ...
Introduction
Postpartum preeclampsia (PPPE) is an under-diagnosed condition, developing within 48 hours to 6 weeks following an uncomplicated pregnancy. The etiology of PPPE is still unknown, leaving patients vulnerable and making the identification and treatment of patients requiring postpartum care an unmet need. We aimed to understand the immune contribution to PPPE at the time of diagnosis, as well as uncover the predictive potential of perinatal biomarkers for the early postnatal identification of high-risk patients.
Methods
Placentas were collected at delivery from uncomplicated pregnancies (CTL) and PPPE patients for immunohistochemistry analysis. In this initial study, blood samples in PPPE patients were collected at the time of PPPE diagnosis (48h-25 days postpartum; mean 7.4 days) and compared to CTL blood samples taken 24h after delivery. Single-cell transcriptomics, flow cytometry, intracellular cytokine staining, and the circulating levels of inflammatory mediators were evaluated in the blood.
Results
Placental CD163+ cells and 1st trimester blood pressures can be valuable non-invasive and predictive biomarkers of PPPE with strong clinical application prospects. Furthermore, changes in immune cell populations, as well as cytokine production by CD14+, CD4+, and CD8+ cells, suggested a dampened response with an exhausted phenotype including decreased IL1β, IL12, and IFNγ as well as elevated IL10.
Discussion
Understanding maternal immune changes at the time of diagnosis and prenatally within the placenta in our sizable cohort will serve as groundwork for pre-clinical and clinical research, as well as guiding clinical practice for example in the development of immune-targeted therapies, and early postnatal identification of patients who would benefit from more thorough follow-ups and risk education in the weeks following an uncomplicated pregnancy.
... (pre-mNK, previously referred to as interferon-producing killer dendritic cells in early reports [84,85]) can be identified upstream of NK1.1/CD3ε gating. Within the CD45R + CD19 À cells that were identified in the first set of lineage gates ( Figure 1B), we found a population of NK1.1 + cells that corresponded with pre-mNKs ( Figure 1F). ...
High‐dimensional immunoprofiling is essential for studying host response to immunotherapy, infection, and disease in murine model systems. However, the difficulty of multiparameter panel design combined with a lack of existing murine tools has prevented the comprehensive study of all major leukocyte phenotypes in a single assay. Herein, we present a 40‐color flow cytometry panel for deep immunophenotyping of murine lymphoid tissues, including the spleen, blood, Peyer's patches, inguinal lymph nodes, bone marrow, and thymus. This panel uses a robust set of surface markers capable of differentiating leukocyte subsets without the use of intracellular staining, thus allowing for the use of cells in downstream functional experiments or multiomic analyses. Our panel classifies T cells, B cells, natural killer cells, innate lymphoid cells, monocytes, macrophages, dendritic cells, basophils, neutrophils, eosinophils, progenitors, and their functional subsets by using a series of co‐stimulatory, checkpoint, activation, migration, and maturation markers. This tool has a multitude of systems immunology applications ranging from serial monitoring of circulating blood signatures to complex endpoint analysis, especially in pre‐clinical settings where treatments can modulate leukocyte abundance and/or function. Ultimately, this 40‐color panel resolves a diverse array of immune cells on the axes of time, tissue, and treatment, filling the niche for a modern tool dedicated to murine immunophenotyping.
... DCs that have been activated by interferon (IFN) generate TRAIL on their surface, that is thought to be implicated in the cytotoxicity of cancer cells. (6) Only monocytes or T cells that have been exposed to IFN-α or IFN-β may display TRAIL on the surface. (7) Function of TRAIL: In response to cytokines, immune effector cells such as NK cells, macrophages, DC, and T cells generate TRAIL on their surfaces, especially IFN-γ, which contains a reaction component of the promoter of the TRAIL gene. ...
... To begin with, radiotherapy triggers the release and presentation of tumor-associated antigens (TAAs), which enhance systemic responses by triggering the recruitment of antigen-presenting cells (APCs), such as macrophages, dendritic cells (DCs), and B cells that enhance T-cell infiltration and promote anti-tumor immune responses in the host [7]. Activation of tumor cells by radiotherapy can reshape the tumor microenvironment to reduce immunotherapy resistance, induce antigen release and cross-presentation of DCs, and trigger the recruitment and activation of APCs, which play a key role in the antitumor immune response [8,9]. Moreover, radiation promotes the release of cytokines and chemokines, which leads to increased production and recruitment of fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), interleukin 1β (IL-1β) and tumor necrosis factor (TNF), which activate Treg cells, bone marrow-derived suppressor cells and cancerassociated fibroblasts [10,11]. ...
Cancer treatment is gradually entering an era of precision, with multitude studies in gene testing and immunotherapy. Tumor cells can be recognized and eliminated by the immune system through the expression of tumor-associated antigens, but when the cancer escapes or otherwise suppresses immunity, the balance between cancer cell proliferation and immune-induced cancer cell killing may be interrupted, resulting in tumor proliferation and progression. There has been significant attention to combining conventional cancer therapies (i.e., radiotherapy) with immunotherapy as opposed to treatment alone. The combination of radio-immunotherapy has been demonstrated in both basic research and clinical trials to provide more effective anti-tumor responses. However, the absolute benefits of radio-immunotherapy are dependent on individual characteristics and not all patients can benefit from radio-immunotherapy. At present, there are numerous articles about exploring the optimal models for combination radio-immunotherapy, but the factors affecting the efficacy of the combination, especially with regard to radiosensitivity remain inconclusive. Radiosensitivity is a measure of the response of cells, tissues, or individuals to ionizing radiation, and various studies have shown that the radiosensitivity index (RSI) will be a potential biomarker for predicting the efficacy of combination radio-immunotherapy. The purpose of this review is to focus on the factors that influence and predict the radiosensitivity of tumor cells, and to evaluate the impact and predictive significance of radiosensitivity on the efficacy of radio-immunotherapy combination.
... Des études récentes ont aussi démontré l'existence d'une sous-population de DCs tueuses impliquée dans la phase d'élimination, les IKDCs hautement sécrétrices d'IFN-γ, de TRAIL et de perforine (Taieb et al., 2006 ;Zitvogel et al., 2006b). (Pardoll, 2002). ...
Le cancer est l’une des principales causes de morbidité et de mortalité dans le monde. L’étude de ses mécanismes a mis en évidence des interactions particulières entre la tumeur et l’immunité adaptative. Les cellules cancéreuses suite à leur transformation maligne expriment des antigènes tumoraux reconnus par les LTs. Ce fondement constitue la base des immunothérapies ciblant les antigènes associés aux tumeurs (TAAs). Parmi les TAAs identifiés, la hTERT apparaît comme un antigène universel, par son implication dans le processus d’oncogenèse et sa surexpression dans 80 à 90% des cancers. Les réponses anti-hTERT trouvées chez des individus sains et des patients cancéreux, témoin d’un répertoire T spécifique préexistant et d’une cassure naturelle de la tolérance, ont orienté nos stratégies vaccinales sur ce TAA. Durant ce doctorat, des stratégies d’immunothérapies basées sur différents produits codant une forme inactive de la hTERT ont été développées. Le premier axe a constitué au développement de vaccins ADN thérapeutiques optimisés à la fois dans leur construction (délétions, réarrangements) et dans leur mode de délivrance. Une procédure d’électroporation a été mise au point afin de les délivrer efficacement dans le derme. Deuxièmement, dans l’optique d’augmenter l’immunogénicité de l’ADN par la réalisation de vaccinations hétérologues ou de créer un produit dérivé, un vecteur rougeole recombinant la hTERT a aussi été développé. Au cours de ce projet, l’immunogénicité et la cytotoxicité des réponses induites par la vaccination pour l’ensemble des constructions ont été démontrées in vivo dans des souris conventionnelles ou transgéniques HLA. De plus, un effet anti-tumoral a aussi été démontré pour le premier produit clinique d’Invectys.
... We first confirmed higher PD-1 expression on NK cells isolated from blood and spleen of tumor-bearing mice using FCM (Fig. 5a). Cell-autonomous protumorigenic effects of endogenous IL-18 have been reported in B16F10 melanoma [28]. Further, human breast cell line MDA-MB-231 promoted the expression of PD-1 by secreting IL-18 [29]. ...
Studies have begun to emerge showing the protumor effects of tumor-associated neutrophils (TANs) in tumorigenesis, which may involve dysfunction of NK cells. However, the mechanism through which these rebellious neutrophils modulate NK cell immunity in tumor-bearing state remains unclear. In the present study, we demonstrate that neutrophils can impair the cytotoxicity and infiltration capability of NK cells, and downregulate CCR1 resulting in the weakened infiltration capability of NK cells. Moreover, neutrophils can decrease the responsiveness of NK-activating receptors, NKp46 and NKG2D. Mechanistically, enhanced PD-L1 on neutrophils and PD-1 on NK cells, and subsequent PD-L1/PD-1 interactions were the main mechanisms determining the suppression of neutrophils in NK cell immunity. G-CSF/STAT3 pathway was responsible for PD-L1 upregulation on neutrophils, while IL-18 was essential for PD-1 enhancement on NK cells. The crosstalk between neutrophils and NK cells was cell-cell interaction-dependent. These findings suggest that neutrophils can suppress the antitumor immunity of NK cells in tumor-bearing status through the PD-L1/PD-1 axis, highlighting the importance of PD-L1/PD-1 in the inhibitory effect of neutrophils on NK cells. Targeting G-CSF/STAT3 and IL-18 signaling pathway may be potential strategies to inhibit residual tumor in tumor therapy.
... Controversy exists regarding the generation as well as phenotypic and functional identification of a subset of NK cells with the effector function of APC-like activity. Several studies have shown that highly proliferative, B220 high NK cells have a DC-like accessory function [12,13]. These cells have multiple names. ...
NK cells, which are composed of phenotypically and functionally heterogeneous subpopulations, play critical roles in immunity against cancer. The mechanism of generation of distinct subsets such as the effector and regulatory subtypes is unclear. Here, we show that this process comprises several steps, including generation of proliferating, highly cytotoxic cells activated by IL-15/IL-18 and differentiation into distinct cell populations induced with IL-12. Freshly prepared murine splenic NK cells expressed IL-15Rs and IL-18Rs and rapidly began to proliferate following stimulation with IL-15/IL-18. The proliferating NK cells highly expressed various activation markers such as B220, CD49b (DX5), lysosome-associated membrane glycoprotein 1 (LAMP-1), DNAX accessory molecule 1, perforin, and granzyme B and showed reduced expression of natural killer cell p46-related protein (NKp46) and IL-18Rα. These cells exerted strong cytotoxicity against YAC-1 cells, but did not secrete cytokines. IL-12 rapidly activated STAT4 in these cells, induced IFN-γ production, and then upregulated p21 and p27, leading to withdrawal from the cell cycle. In parallel, IL-12-stimulated cells gradually reduced cytotoxicity, decreased expression of activation markers, and instead increased expression of Sca-1, CD25, CD49a, and NKp46. Some IL-15/IL-18-induced cells strongly expressed PD-1, whereas NK cells induced with IL-15/IL-18 and IL-12 expressed high levels of T cell immunoglobulin mucin-3, LAG-3, and natural killer group 2 A. Furthermore, these cells spontaneously secreted IL-10 and TGF-β following prolonged incubation. Thus, IL-12 regulates expansion of NK cells activated with IL-15/IL-18, influences the population size of highly cytotoxic cells, and induces differentiation to unique cells sharing some phenotypes of ILCs.
... sponded to maternally ingested linseed oil to inhibit the induction of IFN-γ-producing CD8α + T cells in the progeny pups. To this end, we determined the number of dermal Treg cells in the pups because these cells are known to inhibit skin inflammation, 39 but the cell counts did not differ between the soybean and linseed groups (Figure 2A).We then looked at pDCs, which are reported to exert regulatory functions by producing immunomodulatory factors, including indoleamine 2,3-dioxygenase (IDO), inducible T-cell co-stimulator ligand (ICOSL, which is encoded by Icosl), granzyme B (encoded by Gzmb), TNF-α (encoded by Tnfa), and TNF-related apoptosis-inducing ligand (TRAIL, encoded by Trail).25,[40][41][42] Moreover, pDCs were reported to potentially express inhibitory molecules including programmed death ligand-1 (PD-L1), IL-10, TGF-β1, and CD86.43,44 ...
Background
Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups.
Methods
Contact hypersensitivity (CHS) induced by 2,4‐dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT‐PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC‐MS/MS.
Results
We show that maternal intake of linseed oil, containing abundant ω3 α‐linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14‐lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF‐related apoptosis‐inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA‐derived 14‐lipoxygenation products to mouse pups ameliorated their DNFB CHS.
Conclusion
These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.
... Exposure of immunogenic antigens by mutated or dying cells activates Natural Killer (NK) receptors NKGD and promotes proliferation of infiltrating CD8 + T cells by induction of major histocompatibility complex (MHC) class Ia, resulting in their clearance. In particular, a subset of high Interferon -γ (IFN-γ) secreting NK cells is at the forefront of innate response against cancer and it is responsible for Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL)dependent lysis of tumor cells in mice [26]. Stress or necrosis induced signals, like Danger Associated Molecular Patterns (DAMP), are crucial for stimulating Pattern recognition receptor (PRR), like Toll-like receptor (TLR) and Nod-like receptor (NLR), elective effectors of innate immunity. ...
Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.
In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.
A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient’s prognosis in both TrkA- dependent and independent cancers.
... Here, to our knowledge for the first time we have demonstrated that administration of Imatinib increases intratumoral levels of IL-2 cytokine in lung tumor beds. Therefore, it could be stated that Imatinib may attribute antitumor activity by inducing IL-2 which further enhances the cytotoxic activity of NK cells towards tumor cells (Taieb et al. 2006). On the other hand, IL-4 has been characterized as anti-inflammatory cytokine (Lee et al. 2002) and has also been reported to induce apoptosis in human lung adenocarcinoma cells (Shankaranarayanan and Nigam 2003). ...
Lung cancer has second highest rate of incidence and mortality around the world. Smoking cigarettes is the main stream cause of lung carcinogenesis along with other factors such as spontaneous mutations, inactivation of tumor suppressor genes. The present study was aimed to identify the mechanistic role of Imatinib in the chemoprevention of experimental lung carcinogenesis in rat model. Gross morphological observations for tumor formation, histological examinations, RT-PCR, Western blotting, fluorescence spectroscopy and molecular docking studies were performed to elucidate the chemopreventive effects of Imatinib and support our hypothesis by various experiments. It is evident that immuno-compromised microenvironment inside solid tumors is responsible for tumor progression and drug resistance. Therefore, it is inevitable to modulate the pro-inflammatory signaling inside solid tumors to restrict neoangiogenesis. In the present study, we observed that Imatinib could downregulate the inflammatory signaling and also attributed angiostatic effects. Moreover, Imatinib also altered the biophysical properties of BAL cells such as plasma membrane potential, fluidity and microviscosity to restrict their infiltration and thereby accumulation to mount immuno-compromised environment inside the solid tumors during angiogenesis. Our molecular docking studies suggest that immunomodulatory and angiostatic properties of Imatinib could be either independent of each other or just a case of synergistic pleiotropy. Imatinib was observed to activate the intrinsic or mitochondrial pathway of apoptosis to achieve desired effects in cancer cell killings. Interestingly, binding of Imatinib inside the catalytic domain of PARP-1 also suggests that it has caspase-independent properties in promoting cancer cell deaths.
... After the demonstration in the animal model of host dentritic cell (DC) revertant effect on resistance to IM through the promotion of the NK-celldependent antitumor effect, subsequent studies demonstrate the CD11c+B220+NK1.1+ cells increase during the combination therapy of IM plus IL-2 for the production IFN-γ by contact with tumor cells naming these CD11c+ cells IFN-producing killer DC (IKDC) [9,10]. ...
A male 68 years hold patient was admitted to surgical ward for hemorrhagic shock. After CT scan detection of 6x5 cm neoformation of first jejunal loop, he was submitted to segmental resection and pathological diagnosis was gastrointestinal stromal tumor. The patient was defined as high-risk according to Takahashi criteria, but refused Imatinib adjuvant therapy. After 15 months of disease-free interval, he developed bilobar liver metastases. After treatment with Imatinib 400 mg he reported G3 hepatotoxicity resolved with temporary suspension, he continue low dose with stable disease. After liver progression, he resumed Imatinib full dose with disease stabilization for 9 months. After liver progression, second line Sunitinib 37,5 mg/day was started for four months with stable disease. After further liver and lymph node mediastinal progression he was treated for four months with Regorafenib with disease stabilization. Patient developed slow but inexorable progression of liver disease with severe abdominal pain resistant to opioid and was treated with authorized compassionate program comprising Cyclophosphamide 300 mg/sqm and Fluorouracil 500 mg/sqm on day 1 intravenously followed by Interleukin-2 4.5 MUI subcutaneously on days 3–6 and 17–20 every four weeks. After three cycles the patients obtained a relevant subjective improvement with partial response on mediastinal lymph node and liver stabilization. A substantial increase on neutrophil, lymphocytes, monocytes, platelets, T regulator cells count, and a decrease on platelets/lymphocytes, CD8/T regulator cells ratio, CD8, NK count and C-reactive protein value were observed after treatment compared to basal value. The toxicity was mild represented by fever G1, flue-like-syndrome G1 during the treatment. After four cycle of chemo-immunotherapy, the patient demonstrated progression of disease and died five months after treatment. Noteworthy is the temporal disease control with significant symptomatic improvement achieved for the first time with this chemo-immunotherapeutic combination in a patient with very advanced pretreated GIST.
... Je nach Höhe der Expression des IFN-γ Rezeptors führt dieses über eine Signalkaskade zur Apoptose. Zellen mit hoher Expression, wie beispielsweise myeloische Zellen, sind somit anfälliger gegenüber der IFN-γ induzierten Apoptose[125].Ein sehr wichtiger Effekt von IFN-γ ist der antibakterielle Effekt über Makrophagen.Diese Immunzellen vermehren sich drastisch unter einer Kombinationstherapie mit dem TKI Imatinib + IL-2 und besitzen die Fähigkeit, Tumorzellen zu erkennen und sehr große Mengen IFN-γ zu produzieren[129,130]. Es konnte gezeigt werden, dass die Fähigkeit der IKDCs und pre-mNKs, Tumorzellen zu töten, zum einen indirekt durch die IFN-γ Produktion, zum anderen durch direkte Tumor-Zell-Lyse über den Tumor-Nekrose-Faktor-verwandten Apoptose induzierenden Liganden Die vitalen Tumorzellen der murinen Melanomzelllinie, die die Basis für beinahe jedes Experiment darstellten, wurden in einer bestimmten Zellkultur gehalten. ...
Hintergrund: Tyrosinkinaseinhibitoren (TKIs) stellen einen neuen Weg einer zielgerichteten Therapie in der Onkologie dar. Einige davon werden bereits erfolgreich in der Klinik eingesetzt, so zum Beispiel der TKI Imatinib. Imatinib blockiert zielgerichtet die Tyrosinkinase bcr-abl, die in vielen Fällen ursächlich für die CML ist. In einer Vorarbeit wurde deren Auswirkung und auch die des TKIs Nilotinib auf das Immunsystem untersucht. Ebenso wurde eine Steigerung des therapeutischen Erfolgs durch die Kombination mit dem Zytokin IL-2 erreicht. Ziel dieser Arbeit war es, denselben Effekt auf die Tumorreduktion mithilfe der TKIs Sorafenib und Dasatinib nachzuweisen, sowie auch deren Auswirkung auf bestimmte Zellen des Immunsystems zu analysieren. Hauptaugenmerk liegt hierbei auf den NK-Zellen und deren Subpopulationen. Methoden: Für die in vivo Versuche diente das B16F10 Melanom Modell, in welchem die Mäuse nach Tumorinfiltration jeweils für 10 bis 13 Tage mit einem TKI behandelt wurden. Einerseits wurde die Zahl der sichtbaren Lungenmetastasen ausgewertet und andererseits erfolgte eine durchflusszytometrische Analyse der Immunzellen. Ergebnisse: Letztendlich konnte durch diese Arbeit gezeigt werden, dass der TKI Sorafenib eine vergleichbare Tumorreduktion erzielt, wie das in den Vorarbeiten bereits für Nilotinib gezeigt werden konnte. Diesen Effekt konnte man wiederum mit IL-2 steigern. Der TKI Dasatinib hingegen erwies sich als kaum antitumoral in diesem Modell. Ferner wurde beobachtet, dass reife NK-Zellen unter Kombinationstherapie von Nilotinib und Sorafenib mit jeweils IL-2 zum Tumor migrieren. Die Bedeutung der NK-Zellen bei der antitumoralen Wirkung zeigte sich auch in verschiedenen Untersuchungen mit Knockout-Mäusen, insbesondere mit solchen, die kein IFN-γ bilden. Schlussfolgerung: Es konnte eine signifikante antitumorale Aktivität von Sorafenib, nicht jedoch von Dasatinib, in Kombination mit IL-2 gezeigt werden. Dieser Effekt scheint stark von IFN-γ abhängig zu sein, was zu einem wesentlichen Teil auf die Stimulation reifer NK-Zellen zurückzuführen ist.
... Tumor cell elimination may also be blunted by the immune suppressive barriers overexpression, such as checkpoint receptor signaling (CTLA-4, PD-1/PD-L1) and immunomodulatory cellular subsets [Tregs and myeloidderived suppressor cells (MDSCs)] (20,21). Moreover, there are evidences of defects in both the number and functions of DC subsets, which facilitate tumor progression and immune evasion (22)(23)(24)(25)(26)(27)(28)(29). Overall, the transition of DC from an in vitro cell culture to an in vivo immunosuppressive environment may alter the effectiveness of DC-based immunotherapy. ...
With the advent of combined immunotherapies, personalized dendritic cell (DC)-based vaccination could integrate the current standard of care for the treatment of a large variety of tumors. Due to their proficiency at antigen presentation, DC are key coordinators of the innate and adaptive immune system, and have critical roles in the induction of antitumor immunity. However, despite proven immunogenicity and favorable safety profiles, DC-based immunotherapies have not succeeded at inducing significant objective clinical responses. Emerging data suggest that the combination of DC-based vaccination with other cancer therapies may fully unleash the potential of DC-based cancer vaccines and improve patient survival. In this review, we discuss the recent efforts to develop innovative personalized DC-based vaccines and their use in combined therapies, with a particular focus on ovarian cancer and the promising results of mutanome-based personalized immunotherapies.
... DCs stimulated by interferon-β (IFN-β) express TRAIL on their surface, which is involved in cytotoxicity against tumor cells [49]. IFN-producing killer DCs (IKDCs), which link innate and adaptive immune responses, exhibit cytotoxic activity in part due to the type I IFN-mediated expression of TRAIL [50,51]. Regarding T cells, surface expression of TRAIL can only be detected on activated T cells or monocytes after exposure to IFN-α or IFN-β [52][53][54]. ...
(TNF)-related apoptosis-inducing ligand (TRAIL) is able to activate the extrinsic apoptotic pathway upon binding to DR4/TRAIL-R1 and/or DR5/TRAIL-R2 receptors. Structural data indicate that TRAIL functions as a trimer that can engage three receptor molecules simultaneously, resulting in receptor trimerization and leading to conformational changes in TRAIL receptors. However, receptor conformational changes induced by the binding of TRAIL depend on the molecular form of this death ligand, and not always properly trigger the apoptotic cascade. In fact, TRAIL exhibits a much stronger pro-apoptotic activity when is found as a transmembrane protein than when it occurs as a soluble form and this enhanced biological activity is directly linked to its ability to cluster TRAIL receptors in supra-molecular structures. In this regard, cells involved in tumor immunosurveillance, such as activated human T cells, secrete endogenous TRAIL as a transmembrane protein associated with lipid microvesicles called exosomes upon T-cell reactivation. Consequently, it seems clear that a proper oligomerization of TRAIL receptors, which leads to a strong apoptotic signaling, is crucial for inducing apoptosis in cancer cells upon TRAIL treatment. In this review, the current knowledge of oligomerization status of TRAIL receptors is discussed as well as the implications for cancer treatment when using TRAIL-based therapies.
... Recently, new hybrid immune cell types were identified as IKDCs, which resemble both NK cells and DCs, and were originally described as CD11c int B220 + NK1.1 + CD3 − CD19 − Gr-1 − cells [45,46]. IKDCs exert potent anti-tumor activity through the secretion of IFN-γ and the direct killing of tumor cells [47][48][49]. Data from this study show a significant increase in the percentage of IKDCs that might be involved in anti-tumor activity in the group of mice vaccinated with one dose or three doses of irradiated TC-1/cGM-CSF vaccine compared with that in the group of mice vaccinated with five doses of irradiated TC-1/cGM-CSF vaccine. This implies that five doses of vaccination downregulate the generation of IKDCs compared with three doses. ...
Ectopic expression of codon-modified granulocyte-macrophage colony-stimulating factor (cGM-CSF) in TC-1 cells (TC-1/cGM-CSF), a model cell line for human papillomavirus (HPV)-infected cervical cancer cells, increased the expression level of GM-CSF and improved the efficacy of tumor cell-based vaccines in a cervical cancer mouse model. The number of vaccine doses required to induce a long-term immune response in a cervical cancer mouse model is poorly understood. Here, we investigated one, three, and five doses of the irradiated TC-1/cGM-CSF vaccine to determine which dose was effective in inducing a greater immune response and the suppression of tumors. Our findings showed that three doses of irradiated TC-1/cGM-CSF vaccine elicited slower tumor growth rates and enhanced survival rates compared with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Consistently, mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine exhibited stronger interferon gamma (IFN-γ) production in HPV E7-specific CD8+ T cells and CD4+ T cells. A higher percentage of natural killer cells and interferon-producing killer dendritic cells (IKDCs) appeared in the splenocytes of the mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine compared with those of the mice vaccinated with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Our findings demonstrate that single or multiple vaccinations, such as five doses, with irradiated TC-1/cGM-CSF vaccine suppressed the immune response, whereas three doses of irradiated TC-1/cGM-CSF vaccine elicited a greater immune response and subsequent tumor suppression.
... Recruited from peripheral blood, chemokines and growth factors induce the differentiation of monocytes into M2-polarized macrophages.Factors promoting polarization include cytokines produced by tumor cells (IL-4, IL-10), and cytokines produced by cells of the immune system, like Treg-derived IL-10 and Th2derived IL-4/IL-13. TAMs contribute to immunosuppression with the production of TGFβ and IL-10[81,82]. ...
Glioblastoma is a highly destructive primary brain cancer with poor prognosis despite aggressive treatment consisting of surgical resection, radiation, and chemotherapy. Hence, development of novel treatment strategies represents a continuous need. One treatment approach aims to revert the suppressive tumor microenvironment into a pro- inflammatory microenvironment leading to tumor rejection. Multiple clinical trials are currently ongoing using intratumoral delivery of the pro-inflammatory cytokine interleukin (IL)-12 with the aim of minimizing toxicity while maximizing efficacy. However, improvement of IL-12 based immunotherapy requires an immunological understanding of the mechanistic underpinnings. Using a syngeneic mouse model for glioblastoma, we previously showed that intratumoral delivery of IL-12 leads to tumor rejection. Here we show that tumor control is dependent on IL-12 signaling in tumor- invading (cluster of differentiation 8) CD8+ T cells, driving local expansion. We observed a concomitant influx of myeloid cells into the tumor microenvironment. However, chemokine-receptor 2 (CCR2)-dependent monocyte-derived cells were dispensable for IL-12-mediated tumor rejection. Tumor control was supported by CD103+ dendritic cells (DCs) found within the tumor microenvironment. However, in the absence of CD103+ DCs mice seem to control, but are not able to reject IL-12 expressing tumors. Our findings provide new insights into the mechanism of IL-12 mediated glioma rejection, including requirement of directly and indirectly responsive cell types, to consider for the development of novel treatment strategies. Das Glioblastom ist ein bösartiger Hirntumor, der trotz aggressiver Behandlung bestehend aus chirurgischer Resektion, Strahlentherapie und Chemotherapie schlechte Prognosen aufzeigt. Daher ist es essenziell kontinuierlich neue Behandlungsstrategien zu entwickeln. Ein Behandlungsansatz zielt darauf ab di suppressive Tumormikroumgebung in eine proinflammatorische Mikroumgebung umzuwandeln, die zur Abstossung des Tumors führt. Aktuelle klinische Studien basieren auf der intratumoralen Verabreichung des pro-inflammatorischen Zytokin Interleukin (IL) -12. Das Ziel ist, die Toxizität zu minimieren und gleichzeitig die therapeutische Wirksamkeit zu maximieren. Voraussetzung für die Entwicklung der IL-12-basierten Immuntherapie ist das Verständnis der grundlegenden immunologischen Mechanismen. Mit einem Mausmodell für das Glioblastom konnten wir nachweisen, dass die intratumorale Verabreichung von IL-12 zur Tumorabstossung führt. In der vorliegenden Studie zeigen wir, dass die IL-12 induzierte Tumorkontrolle von der Wirkung auf tumor-infiltrierende CD8+ T-Zellen basiert und zu deren Expansion führt. Gleichzeitig war eine Anhäufung von myeloiden Zellen in der Tumormikroumgebung zu beobachten, wobei CCR2-abbhängige monozytische Zellen für die IL-12 vermittelte Tumorabstossung entbehrlich waren. Die Tumorkontrolle wird von CD103+ dendritischen Zellen innerhalb der Tumormikroumgebung unterstützt, wobei in Abwesenheit von CD103+ dendritischen Zellen eine Tumorkontrolle, aber keine Abstossung von IL-12 überexprimierenden Tumoren stattfindet. Unsere Ergebnisse liefern neue Erkenntnisse über den Mechanismus der IL-12- vermittelten Gliomabstossung, einschliesslich der direkt und indirekt involvierten Zelltypen, die für die Entwicklung neuer Therapiestrategien Berücksichtigtung finden sollten.
... A subpopulation of DCs has been defined as interferon-370 producing killer DCs (IKDCs), characterized by a CD11c +intermediate , NK1.1 + , CD49b + , B220 + , Ly6G − phenotype, and by the killing of various tumor cell lines in a TRAILdependent fashion. 59 These cells can produce both IFN-γ and IFN-α. We found that neither CD11c + CD40 + iDCs nor 375 CD11c + CD40 + mDCs expressed NK1.1 or NKG2D (except for a minor subpopulation (< 7%) of mDCs that expressed NKG2D (± IFN-γ) (Figure 6(c)). ...
Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8+ T-cells, and natural killer (NK)1.1+ cells, that express granzyme B associated with Lamp-1 and IFN-γ. Efficacy of iDC-vaccination was CD8+ T-cell-dependent but NK1.1+ cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses. We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC.
... Because these CD1c + CD14 + cells were phenotypically distinct from MonoMacs, and because they had not been systematically distinguished in published studies 34 , we call them 'CD14 + DCs' here. CD56 + CD14 + cells were reported to be interferon-producing killer DCs in the context of cancer 35 and were subsequently shown to correspond to activated natural killer cells 36 . A similar CD56 + CD14 + phenotype has been described for fraction of blood monocytes from healthy donors 37 . ...
The functions and transcriptional profiles of dendritic cells (DCs) result from the interplay between ontogeny and tissue imprinting. How tumors shape human DCs is unknown. Here we used RNA-based next-generation sequencing to systematically analyze the transcriptomes of plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 conventional DCs (cDC1s), type 2 conventional DCs (cDC2s), CD14+ DCs and monocytes-macrophages from human primary luminal breast cancer (LBC) and triple-negative breast cancer (TNBC). By comparing tumor tissue with non-invaded tissue from the same patient, we found that 85% of the genes upregulated in DCs in LBC were specific to each DC subset. However, all DC subsets in TNBC commonly showed enrichment for the interferon pathway, but those in LBC did not. Finally, we defined transcriptional signatures specific for tumor DC subsets with a prognostic effect on their respective breast-cancer subtype. We conclude that the adjustment of DCs to the tumor microenvironment is subset specific and can be used to predict disease outcome. Our work also provides a resource for the identification of potential targets and biomarkers that might improve antitumor therapies.
... IKDCs, were able to lyse various target cells in the absence of NKG2D ligands or MHC class I molecules. Adoptive transfer of IKDCs but not B220− NK cells delayed tumor growth (113). Balachandran et al. (114) demonstrated the pre-existing role of CD8+ -mediated immune response, which is enhanced by imatinib therapy. ...
Tumor ablation by thermal, chemical and radiological sources has received substantial attention for the treatment of many localized malignancies. The primary goal of most ablation procedures is to eradicate all viable malignant cells within a designated target volume through the application of energy or chemicals. Methods such as radiotherapy, chemical and biological ablation, photodynamic therapy, cryoablation, high-temperature ablation (radiofrequency, microwave, laser, and ultrasound), and electric-based ablation have been developed for focal malignancies. In recent years a large volume of data emerged on the effect of in situ tumor destruction (ablation) on inflammatory and immune components resulting in systemic anti-tumor reactions. It is evident that in situ tumor ablation can involve tumor antigen release, cross presentation and the release of DAMPS and make the tumor its own cellular vaccine. Tumor tissue destruction by in situ ablation may stimulate antigen-specific cellular immunity engendered by an inflammatory milieu. Dendritic cells (DCs) attracted to this microenvironment, will undergo maturation after internalizing cellular debris containing tumor antigens and will be exposed to damage associated molecular pattern (DAMP). Mature DCs can mediate antigen-specific cellular immunity via presentation of processed antigens to T cells. The immunomodulatory properties, exhibited by in situ ablation could portend a future collaboration with immunotherapeutic measures. In this review are summarized and discuss the preclinical and clinical studies pertinent to the phenomena of stimulation of specific anti-tumor immunity by various ablation modalities and the immunology related measures used to boost this response.
... Such cells are natural killer T cells (NKT), which express αβ TCR and NK cell receptors, and innate-like γδ T cells, whose antigen recognition by γδ TCR-is not restricted to major histocompatibility complex (MHC) molecules [13,14]. Th22 IFN-γ + CD4 + T cells, macrophages, IFN-producing killer dendritic cells (IKDC) and group 1 innate lymphoid cells (ILC1) are some of the recently discovered immune cells found to infiltrate tumors and to produce IFN-γ [15][16][17][18]. With revived scientific interest for studying immune components of tumor microenvironments, the list of IFN-γ producers is expected to be further expanded. ...
Interferon-γ (IFN-γ) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-γ, it has also been involved in promoting an outgrowth of tumor cells with immunoevasive phenotype suggesting an existence of a dark “tumor-promoting” side effect of IFN-γ. In this review, we will summarize this multi-functional role of IFN-γ in tumor context, how it promotes changes in tumor phenotype towards increased fitness for growth in immunocompetent host. Furthermore, we summarize how IFN-γ is involved in homeostatic or cancer-triggered mechanisms to establish an immunosuppressive tumor microenvironment.
... 48 In addition to NK cells, another subset of immune cells can also produce IFN-γ and mediate TRAIL-dependent lysis of tumor cells. 49 Oncolytic viruses (OVs) have also been recognized as a potent NK cell activator, and these NK cells enhance OV to clear tumors in various instances. 50 In short, such immunological findings may suggest that a circadian crosstalk was created by OAd, ING4 and TRAIL to efficiently recruit cytotoxic NK cells and overproduce IFN-γ in the tumor tissues. ...
Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4); as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); as potent-apoptosis inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono-and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce anti-tumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.
Immunotherapy and targeted therapy have emerged as promising therapeutic options for cancer patients. Immunotherapies induce a host immune response that mediates long-lived tumor destruction, while targeted therapies suppress molecular mechanisms that are important for tumor maintenance and growth. In addition, cytotoxic agents and targeted therapies regulate immune responses, which increases the chances that these therapeutic approaches may be efficiently combined with immunotherapy to ameliorate clinical outcomes. Various studies have suggested that combinations of therapies that target different stages of anti-tumor immunity may be synergistic, which can lead to potent and more prolonged responses that can achieve long-lasting tumor destruction. Nurses associated with cancer patients should have a better understanding of the immunotherapies and targeted therapies, such as their efficacy profiles, mechanisms of action, as well as management and prophylaxis of adverse events. Indeed, this knowledge will be important in establishing care for cancer patients receiving immunotherapies and targeted therapies for cancer treatment. Moreover, nurses need a better understanding regarding targeted therapies and immunotherapies to ameliorate outcomes in patients receiving these therapies, as well as management and early detection of possible adverse effects, especially adverse events associated with checkpoint inhibitors and various other therapies that control T-cell activation causing autoimmune toxicity. Nurses practice in numerous settings, such as hospitals, home healthcare agencies, radiation therapy facilities, ambulatory care clinics, and community agencies. Therefore, as compared to other members of the healthcare team, nurses often have better opportunities to develop the essential rapport in providing effective nurse-led patient education, which is important for effective therapeutic outcomes and continuance of therapy. In this article, we have particularly focused on providing a detailed overview on targeted therapies and immunotherapies used in cancer treatment, management of their associated adverse events, and the impact as well as strategies of nurse-led patient education.
Interferon-gamma (IFN-γ) has been identified as a crucial factor in determining the responsiveness to immunotherapy. Produced primarily by natural killer (NK) and T cells, IFN-γ promotes activation, maturation, proliferation, cytokine expression, and effector function in immune cells, while simultaneously inducing antigen presentation, growth arrest, and apoptosis in tumor cells. However, tumor cells can hijack the IFN-γ signaling pathway to mount IFN-γ resistance: rather than increasing antigenicity and succumbing to death, tumor cells acquire stemness characteristics and express immunosuppressive molecules to defend against antitumor immunity. In this review, we summarize the potential mechanisms of IFN-γ resistance occurring at two critical stages: disrupted signal transduction along the IFNG/IFNGR/JAK/STAT pathway, or preferential expression of specific interferon-stimulated genes (ISGs). Elucidating the molecular mechanisms through which tumor cells develop IFN-γ resistance help identify promising therapeutic targets to improve immunotherapy, with broad application value in conjugation with targeted, antibody or cellular therapies.
Radiotherapy is one of the mainstays of cancer treatment. More than half of cancer patients receive radiation therapy. In addition to the well-known direct tumoricidal effect, radiotherapy has immunomodulatory properties. When combined with immunotherapy, radiotherapy, especially high-dose radiotherapy (HDRT), exert superior systemic effects on distal and unirradiated tumors, which is called abscopal effect. However, these effects are not always effective for cancer patients. Therefore, many studies have focused on exploring the optimized radiotherapy regimens to further enhance the antitumor immunity of HDRT and reduce its immunosuppressive effect. Several studies have shown that low-dose radiotherapy (LDRT) can effectively reprogram the tumor microenvironment, thereby potentially overcoming the immunosuppressive stroma induced by HDRT. However, bridging the gap between preclinical commitment and effective clinical delivery is challenging. In this review, we summarized the existing studies supporting the combined use of HDRT and LDRT to synergistically enhance antitumor immunity, and provided ideas for the individualized clinical application of multimodal radiotherapy (HDRT+LDRT) combined with immunotherapy.
Hepatocellular carcinoma (HCC) remains a public health challenge that requires dedication to develop new treatment options due to its high recurrence rate and poor prognosis. Interferon-producing killer dendritic cell (IKDC) is a subset of INF-γ secreting immune cells that modulates acquired immunity and possesses cytolytic ability. We modified IKDC isolated from the murine spleen with T-bet lentiviral transduction to enhance its cytotoxicity against HCC, and acquired IKDC overexpressing T-bet (T-bet-IKDC) for the first time. T-bet-IKDC has increased INF-γ secretion and surface expression of NKG2D and TRAIL. In vitro study by MTS assay and flow cytometry showed enhanced anti-tumor effect against H22 cells via apoptosis induction in a dose- and time-dependent manner. In vivo study on H22-bearing mice confirmed increased INF-γ secretion, reduced tumor size, increased caspase 3 cleavage, and up-regulation of cytotoxic molecules after T-bet-IKDC administration. The study suggested prospective application of T-bet-IKDC in future immunotherapy for HCC treatment.
Recent global incidences and mortality rates have placed colorectal cancer (CRC) at third and second positions, respectively, among both sexes of all ages. Resistance during chemotherapy is a big problem in the treatment and disease-free survival of CRC patients. Discovery of new anticancer drug(s) is a time taking process and therefore, invites studies for repurposing the known therapeutics. The present study was conceived to analyze the anticancer role of Imatinib in experimental CRC at early stages. Different experimental procedures e.g. tumor incidences or histoarchitectural changes, gene and protein expression analysis, estimations of intracellular calcium, ROS, mitochondrial membrane potential, apoptotic index and molecular docking was performed to support the hypothesis. It was observed that Imatinib could function as an immunomodulator by breaking the feed-back loop between the proinflammatory cytokines (IL-1β and TNF-α) and transcription factors (NF-κB, Jak3/Stat3) knowingly involved in increased cell proliferation during tumorigenesis via activating different intracellular signaling. Also, Imatinib could independently deregulate the other cell survival and proliferation signaling e.g. PI3-K/Akt/mTOR, Wnt/β-catenin and MAPK. Proinflammatory cytokines orchestrated intracellular signaling also involve angiogenic factors to be upregulated during CRC which were also seemed to be independently suppressed by Imatinib. Restoration of physiological apoptosis by increasing the release of intracellular calcium to generate ROS thereby reducing the mitochondrial membrane potential for the release of cytochrome c and activation of caspase-3 was also reported with Imatinib administration. Thus, it may be suggested that Imatinib show synergistic pleiotropy in suppressing the interlinked tumorigenic signaling pathways independently.
Immune cells act together to maintain host integrity against infections. In a cancer setting, immune cells initially attempt to eliminate transformed cells. However, if this fails the tumor microenvironment can subvert the anticancer immune response, leading to cancer outgrowth. The balance between effector and regulatory immune cells in the tumor microenvironment has been shown to profoundly affect the prognosis of cancer patients. While it was clear that autophagy, a catabolic process responsible for protein degradation, was affecting the biology of cancer cells, accumulating evidence suggests that autophagy controls the function of immune cells in the tumor microenvironment. After discussing the contribution of tumor-infiltrating cells in cancer progression, we will herein review the contribution of autophagy to the biology of tumor-infiltrating immune cells.
B-cell development is initiated by the stepwise differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating the mature B-cells that mediate protective immunity. This highly regulated process also generates clonal immunological diversity via recombination of immunoglobulin genes. While several transcription factors that control B-cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene (Erg) is essential for the earliest steps in B-cell differentiation. Erg initiates a transcriptional network involving the B-cell lineage defining genes, Ebf1 and Pax5 , that directly promotes the expression of key genes involved in V(D)J recombination and formation of the B-cell receptor. Complementation of the Erg-deficiency with a productively rearranged immunoglobulin gene rescued B-cell development, demonstrating that Erg is an essential and exquisitely stage specific regulator of the gene regulatory network controlling B-lymphopoiesis.
Lymphocytes and their secreted cytokines play a critical role in tumor control and elimination. In a variety of tumor models, Interleukin-12 has been shown to repress tumor growth. The tumoricidal activity of IL-12 is widely held to be mediated by the activation and polarization of NK and type 1 T helper cells respectively. The purpose of this project was to specifically determine the precise mechanism by which IL-12 mediates tumor suppression rather than investigating its potential clinical application. By systematic analysis of the immune response to an Interleukin-12 secreting melanoma cell line (B16-F10) we found that tumor suppression is mediated independently of T lymphocytes or NK cells. We discovered that IL-12 initiates powerful local anti-tumor immunity by stimulating a subset of lymphoid tissue inducer cells dependent on the transcription factor RORyt. This report not only attributes a clear novel function to this only recently identified cell type in tumor immunology but also raises the possibility of therapeutically stimulating RORyt-dependent lymphoid tissue inducer cells in tumors as a new strategy for the eradication of solid tumors in patients. Lymphozyten und deren sekretierten Zytokine spielen eine wichtige Rolle bei der Kontrolle und Eliminierung von Tumoren. In vielen verschiedenen Tumor-Modellen wurde gezeigt, dass Interleukin- 12 die Fähigkeit besitzt, das Tumorwachstum zu unterdrücken. Diese anti-tumor Aktivität von Interleukin-12 wird weitgehend der Aktivierung und Polarisierung von NK Zellen und Typ 1 Helfer Zellen zugeschrieben. Das Ziel dieses Projekts war in erster Linie das Analysieren des präzisen IL-12- vermittelten Mechanismus welcher zur Unterdrückung des Tumorwachstums führt und nicht das Erforschen einer potentiellen klinischen Applizierung für eine neue Therapie. Als Model verwendeten wir eine Melanoma-Zelllinie (B16-F10) die stetig Interleukin-12 sekretiert. Durch systematisches analysieren der Immunantwort nach Injektion dieser Zelllinie in die Maus haben wir herausgefunden, dass die daraus folgenden Tumor-Unterdrückung unabhängig von T Lymphozyten oder NK Zellen erfolgt. Stattdessen konnten wir zeigen, dass IL-12 eine starke lokale anti-tumor Immunantwort hervorruft indem ein spezifischer Zelltyp der zur Klasse der Lymphgewebe-Induzierer Zellen gehört stimuliert wird. Dieser Zelltyp ist abhängigen von dem Transkriptionsfaktor RORyt. Unsere Arbeit beschreibt nicht nur eine klare neue Funktion für diesen erst kürzlich entdeckten Zelltyp im Rahmen der Tumorimmunologie, sondern erbringt auch neue Möglichkeiten für therapeutische Maßnahmen durch die Stimulierung von RORyt-abhängigen Lymphgewebe-Induzierer Zellen im Tumor als neue Strategie für die Vernichtung von festen Tumoren in Patienten.
Senescence is an important p53-controlled tumor suppressor program that not only opposes the proliferation of cancer cells but also promotes their immune-mediated clearance in certain contexts. In hepatocellular cancer, p53 induction promotes an innate immune cell-mediated clearance of senescent cells wherein natural killer (NK) cells seem to play the primary sentinel role. Whether NK cells also surveil cancer cells in other tumor types when p53 is activated to promote a senescence response is unknown. To identify the role that NK and other innate immune cell types have on the surveillance and destruction of lung adenocarcinoma cells, we developed an orthotopic transplantation model where p53 gene function could be restored to induce senescence after successful engraftment of tumor cells in the mouse lung. Contrary to precedent, we found that NK cells actually limited the efficient clearance of tumor cells from the mouse lung after p53 restoration. Instead, activation of p53 induced the infiltration of monocytes, neutrophils, and interstitial macrophages. Loss of NK cells further promoted expansion of these inflammatory cell types and tumor clearance after p53 restoration. These observations suggest that NK cell responses to p53 activation in lung adenocarcinoma is distinct from those found in other tumor types and that diverse innate immune cell populations may play context-dependent roles during tumor immune surveillance. Further, our data provide an impetus to understand the broader mechanisms that regulate cancer cell destruction by multiple cell types of the innate immune system and distinct cancer contexts.
Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal-leukemic hematopoietic cell out-competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T-cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56/CD3/CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin-like-2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56high NK cells expressing CRTAM and endowed with an exhaustion-like phenotype and the functional capability of producing IL-10 and TGF-β in vitro. Our findings suggest, for the first time, that the tumor microenvironment in ALL directly contribute to exhaustion of NK cell functions by the CRTAM/Necl-2 interaction, and that the potential regulatory role of exhausted-like NK cells may favor malignant progression at the expense of anti-tumor responses. Phenotypic and functional identity of this unique suppressor-like NK cell population within the leukemic BM would be of special interest for the pathobiology of ALL and development of targeting strategies.
L’infection par le virus de la grippe, ou le Myxovirus influenzae de type A (IAV), constitue l'une des causes les plus importantes de maladies des voies respiratoires dans le monde. Elle conduit également à des épidémies récurrentes avec des taux élevés de morbidité et de mortalité. Des surinfections bactériennes, principalement causées par Streptococcus pneumoniae (pneumonie), sont souvent associées à la grippe et contribuent de manière significative à l’excès de mortalité. La perturbation de l'intégrité des tissus pulmonaires et la diminution de l'immunité antibactérienne au cours de l'infection par IAV sont à l’origine de la colonisation et à la dissémination des bactéries.L'infection grippale entraîne une altération profonde du compartiment de cellules myéloïdes pulmonaires caractérisée par une altération numérique ou fonctionnelle des cellules sentinelles - les macrophages alvéolaires et les cellules dendritiques conventionnelles (cDC) - et par un recrutement de cellules myéloïdes inflammatoires -les neutrophiles, les monocytes inflammatoires ou encore les cellules dendritiques inflammatoires.Les cellules myéloïdes sont originaires de la moelle osseuse (MO). Lors d’infections, la myélopoïèse peut être profondément affectée afin de maintenir la production et la mobilisation de cellules myéloïdes inflammatoires au niveau du site d’infection. A l’heure actuelle, les conséquences de l’infection grippale sur la myélopoïèse restent encore mal connues.Dans notre projet, nous rapportons que l'infection grippale conduit à une diminution transitoire du nombre de cDC (cDC1 et cDC2) dans les poumons qui coïncide avec une chute dans la MO, du nombre de progéniteurs/précurseurs impliqués dans la génération des cDC (CDP, pre-cDC et plus particulièrement les pre-cDC1). Cette diminution de la "DCpoïèse" est associée à une accélération de la génération des monocytes, i.e. monopoïèse. La différenciation altérée des cDC est indépendante des cytokines pro-inflammatoires et n'est pas due à un dysfonctionnement intrinsèque des précurseurs de cDC. De façon intéressante, nous rapportons que ces altérations au niveau de la MO sont associées à une diminution de la production de Flt3-L ou Fms-like tyrosine kinase 3 ligand, un facteur crucial pour la différenciation des DC. La supplémentation en Flt3-L au cours de la grippe rétablit la différenciation des progéniteurs de cDC dans la MO et restaure le compartiment des cDC pulmonaires. De façon intéressante, cette restauration s’accompagne d’une protection partielle contre l’infection pneumococcique secondaire caractérisée par une réduction de la charge bactérienne, une amélioration de la pathologie pulmonaire et une survie prolongée.
Metastasis from most adult solid tumors generally has been considered to be widespread and incurable. Here, I present clinical and molecular data to support the hypothesis that some metastases are limited in number and pace and are curable with ablative therapies. I advance the hypothesis that immunotherapy combined with radiotherapy may be a general strategy to increase the number of patients with metastatic cancer amenable to cure. I further suggest that, in the context of ablative radiotherapy, the potential synergies between immunotherapy and radiotherapy are principally within the local tumor microenvironment and require treatment of all or most sites of metastatic disease. Improvements in the molecular staging of metastasis, immunotherapy strategies, and radiotherapy delivery are likely to improve outcomes for patients with metastatic cancer.
NK cells are members of the innate immunity and play a central role in the defense against viral infections and cancer development, but also contribute to triggering and shaping adaptive immune responses. Human NK cells may express MHC II and costimulatory molecules, including CD86, CD80, and OX40 ligand, which allows them to stimulate the CD4⁺ T-cell response. In contrast, murine NK cells do not express MHC II or costimulatory molecules. Upon activation, mouse NK cells can acquire these molecules from dendritic cells (DCs) via intercellular membrane transfer, which leads to suppression of DC-induced CD4⁺ T-cell responses rather than stimulation of T-cell responses. Previous studies showed that porcine NK cells can express MHC II molecules, but it was unknown if porcine NK cells also express costimulatory molecules and whether NK cells may affect T-cell proliferation. We found that primary porcine NK cells express functional MHC II molecules and costimulatory CD80/86, particularly upon activation with IL-2/IL-12/IL-18, and that they are able to stimulate T-cell proliferation. In addition, we show that porcine NK cells are able to internalize antigens derived from killed target cells in an actin polymerization-dependent process. All together, these results indicate that porcine NK cells possess properties associated with APCs, which allows them to stimulate T-cell proliferation.
The aim of chemotherapy and radiotherapy is to eliminate tumor cells. While the outcomes of these cytotoxic treatments were previously attributed to their direct effects on tumor cells, it is now clear that the host’s immune system, and specifically T cells, also contributes to the success of these therapies. These observations, along with the demonstrated clinical successes of anticancer agents targeting T cells have prompted scientists to revisit the mechanisms responsible for T cell polarization. In 1986, Mossman and Coffman have reported the ability of naive CD4 T cells to differentiate into specialized variants, designed as Th1 and Th2 and differing in their profiles of lymphokine activities. Since then, it was shown that both CD4 and CD8 T cells could differentiate in a myriad of effector T cell subsets that have a profound impact on adaptive immunity. In this chapter, we review the molecular mechanisms responsible for the differentiation of T cells and their relevance for human disease.
Bone metastasis is a fatal consequence of a subset of solid malignancies that fail to respond to conventional therapies. While a myriad of factors contribute to osteotropism and disseminated cell survival and outgrowth in bone, efforts to inhibit tumor cell growth in the bone-metastatic niche have largely relied on measures that disrupt the bi-directional interactions between bone resident and tumor cells. However, the targeting of isolated stromal interactions has proven ineffective to date in inhibiting bone-metastatic progression and patient mortality. Osteoimmune regulation is now emerging as a critical determinant of metastatic growth in the bone microenvironment. While this has highlighted the importance of innate immune populations in dictating the temporal development of overt bone metastases, the osteoimmunological processes that underpin tumor cell progression in bone remain severely underexplored. Along with tumor-intrinsic alterations that occur specifically within the bone microenvironment, innate osteoimmunological crosstalk poses an exciting area of future discovery and therapeutic development. Here we review current knowledge of the unique exchange that occurs between bone resident cells, innate immune populations and tumor cells that leads to the establishment of a tumor-permissive milieu.
What's in a drop of blood?
Blood contains many types of cells, including many immune system components. Immune cells used to be characterized by marker-based assays, but now classification relies on the genes that cells express. Villani et al. used deep sequencing at the single-cell level and unbiased clustering to define six dendritic cell and four monocyte populations. This refined analysis has identified, among others, a previously unknown dendritic cell population that potently activates T cells. Further cell culture revealed possible differentiation progenitors within the different cell populations.
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed by in vitro acti- vated natural killer (NK) cells, but the relevance of this observation to the biological function of NK cells has been unclear. Herein, we have demonstrated the in vivo induction of mouse TRAIL expression on various tissue NK cells and correlated NK cell activation with TRAIL- mediated antimetastatic function in vivo. Expression of TRAIL was only constitutive on a sub- set of liver NK cells, and innate NK cell control of Renca carcinoma hepatic metastases in the liver was partially TRAIL dependent. Administration of therapeutic doses of interleukin (IL)-12, a powerful inducer of interferon (IFN)- g production by NK cells and NKT cells, upregulated TRAIL expression on liver, spleen, and lung NK cells, and IL-12 suppressed metastases in both liver and lung in a TRAIL-dependent fashion. By contrast, a -galactosylceramide ( a -GalCer), a powerful inducer of NKT cell IFN- g and IL-4 secretion, suppressed both liver and lung me- tastases but only stimulated NK cell TRAIL-mediated function in the liver. TRAIL expression was not detected on NK cells from IFN- g -deficient mice and TRAIL-mediated antimetastatic effects of IL-12 and a -GalCer were strictly IFN- g dependent. These results indicated that TRAIL induction on NK cells plays a critical role in IFN- g -mediated antimetastatic effects of IL-12 and a -GalCer.
Beta 2-Microglobulin-deficient (beta 2m -/-) mice are reported to lack cell surface expression of major histocompatibility complex (MHC) class I molecules, CD8+ T cells, and the ability to mount MHC class I-specific T cell responses. We have observed that beta 2m -/- mice possess CD8+ T cells that can be induced to perform strong allospecific cytotoxic responses against nonself-MHC class I by in vivo priming. We report that these beta 2m -/- cytotoxic T lymphocyte (CTL) differ from those induced in beta 2m-positive littermates in that they cross-react and kill cells expressing self-MHC class I at normal ligand density with beta 2m. beta 2m -/- CTL could even be induced in primary mixed lymphocyte culture by self-MHC class I expressing stimulator cells, whereas allogeneic stimulator cells failed to elicit a response under similar conditions. Cells with a reduced cell surface MHC class I expression were less sensitive, while syngeneic beta 2m -/- cells were resistant to the beta 2m -/- CTL. This antiself-MHC reactivity could not be induced when beta 2m -/- T cells matured in an environment with normal MHC class I expression in bone marrow chimeric mice. Antiself-MHC reactivity was also observed against human peptide loading-deficient cells expressing the appropriate murine class I molecules, suggesting that affinity to self-MHC class I may occur irrespective of peptide content. The results fit with a model where positive and negative selection of CD8+ T cells in beta 2m -/- mice is mediated by low levels of MHC class I free heavy chains. In this model, low ligand density on selecting cells leads to positive selection of rare T cells that bind to low levels of MHC class I free heavy chains, resulting in a very small peripheral CD8+ compartment. Due to low density of the selecting ligand, negative selection does not remove T cells recognizing beta 2m-positive cells expressing self-MHC class I at normal ligand density, which generates a T cell repertoire that would be autoreactive in a beta 2m-positive littermate. The first "MHC deficient" animals thus paradoxically provide a tool for direct demonstration and analysis of self MHC bias in the T cell repertoire.
Interferon (IFN)-gamma, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow- derived macrophages (BMMPhi) secrete large amounts of IFN-gamma upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-gamma mRNA transcripts, the combined stimulation of BMMPhi with both cytokines leads to the efficient production of IFN-gamma protein. The macrophage-derived IFN-gamma is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-gamma but also a potent IFN-gamma-producing cell.
We investigated the role of antigen-presenting cells in early interferon (IFN)-gamma production in normal and recombinase activating gene 2-deficient (Rag-2(-/-)) mice in response to Listeria monocytogenes (LM) infection and interleukin (IL)-12 administration. Levels of serum IFN-gamma in Rag-2(-/-) mice were comparable to those of normal mice upon either LM infection or IL-12 injection. Depletion of natural killer (NK) cells by administration of anti-asialoGM1 antibodies had little effect on IFN-gamma levels in the sera of Rag-2(-/-) mice after LM infection or IL-12 injection. Incubation of splenocytes from NK cell-depleted Rag-2(-/-) mice with LM resulted in the production of IFN-gamma that was completely blocked by addition of anti-IL-12 antibodies. Both dendritic cells (DCs) and monocytes purified from splenocytes were capable of producing IFN-gamma when cultured in the presence of IL-12. Intracellular immunofluorescence analysis confirmed the IFN-gamma production from DCs. It was further shown that IFN-gamma was produced predominantly by CD8alpha+ lymphoid DCs rather than CD8alpha- myeloid DCs. Collectively, our data indicated that DCs are potent in producing IFN-gamma in response to IL-12 produced by bacterial infection and play an important role in innate immunity and subsequent T helper cell type 1 development in vivo.
Measles virus infection induces a profound immunosuppression that can lead to serious secondary infections. Here we demonstrate
that measles virus induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression in
human monocyte-derived dendritic cells. Moreover, measles virus-infected dendritic cells are shown to be cytotoxic via the
TRAIL pathway.
Mouse splenic dendritic cells (DCs) produce IFN-gamma in response to IL-12. In the present study, we analyzed effects of Th1 and Th2 cytokines on IFN-gamma production by DCs. IL-18 produced by DCs and macrophages acts in an autocrine manner and augments IL-12-induced IFN-gamma production by DCs as also observed in T and NK cells. Surprisingly, IL-4, a Th2 cytokine, also acts synergistically with IL-12 on IFN-gamma production by DCs. In addition, IL-4 markedly enhances IFN-gamma production when DCs are stimulated through CD40 or MHC class II. These results indicate that both Th1 and Th2 cytokines act on DCs during T cell-DC interaction upon Ag presentation. p38 mitogen-activated protein kinase is constitutively activated in mature DCs and is required for IFN-gamma production by DCs. IL-18 but not IL-4 or IL-12 further activates the p38 mitogen-activated protein kinase activity, suggesting that IL-4 and IL-18 enhance IFN-gamma production through distinct intracellular signal transduction pathways in DCs.
Dendritic cells (DCs) are a rare population of leukocytes specialized in Ag processing and presentation to T cells. We have previously shown that cultured rat splenic DCs exhibit a cytotoxic activity against selected target cells. In this study, we analyzed this function in DCs freshly prepared from lymphoid organs using the DC-specific OX62 mAb and magnetic beads. Freshly extracted splenic DCs, but not lymph node and thymic DCs, exhibited a strong and moderate cytotoxic activity against YAC-1 and K562 target cells, respectively. FACS analyses showed that spleen contained a minor subset (10-15%) of CD4(+) and class II(int) DCs that also expressed the OX41 Ag and the lymphoid-related Ags CD5 and CD90 (Thy-1) and a major (80-85%) subset of CD4(-)/OX41(-)/CD5(-) and class II(int) DCs. The cytotoxic activity of splenic DCs was strictly restricted to the CD4(-) DCs, a subset poorly represented in LN and thymus. Contrasting with our previous report using cultured splenic DCs, freshly isolated splenic DCs killed YAC-1 cells using a Ca(2+)-independent mechanism, but this function did not appear mediated by Fas ligand, TNF-related apoptosis-inducing ligand, or TNF-alpha. Therefore, rat DCs contain a subset of naturally cytolytic cells that could play a role in both innate and acquired immune responses. Together with our previous report, these data suggest that rat DCs can use two mechanisms of cytotoxicity depending on their maturation/activation state.
Natural killer (NK) cells attack many tumour cell lines, and are thought to have a critical role in anti-tumour immunity; however, the interaction between NK cells and tumour targets is poorly understood. The stimulatory lectin-like NKG2D receptor is expressed by NK cells, activated CD8+ T cells and by activated macrophages in mice. Several distinct cell-surface ligands that are related to class I major histocompatibility complex molecules have been identified, some of which are expressed at high levels by tumour cells but not by normal cells in adults. However, no direct evidence links the expression of these 'induced self' ligands with tumour cell rejection. Here we demonstrate that ectopic expression of the murine NKG2D ligands Rae1beta or H60 in several tumour cell lines results in potent rejection of the tumour cells by syngeneic mice. Rejection is mediated by NK cells and/or CD8+ T cells. The ligand-expressing tumour cells induce potent priming of cytotoxic T cells and sensitization of NK cells in vivo. Mice that are exposed to live or irradiated tumour cells expressing Rae1 or H60 are specifically immune to subsequent challenge with tumour cells that lack NKG2D ligands, suggesting application of the ligands in the design of tumour vaccines.
Immunization can prevent tumor growth, but the effector cells directly responsible for tumor cell killing in immunized hosts remain undetermined. The present study compares tumor grafts that progress in naive syngeneic rats with the same grafts that completely regress in hosts preimmunized with an immunogenic cell variant. The progressive tumors contain only a few macrophages that remain at the periphery of the tumor without direct contact with the cancer cells. These macrophages do not kill tumor cells in vitro. In contrast, tumors grafted in immunized hosts and examined at the beginning of tumor regression show a dramatic infiltration with mature macrophages, many of them in direct contact with the cancer cells. These macrophages are strongly cytotoxic for the tumor cells in vitro. In contrast to macrophages, tumor-associated lymphocytes are not directly cytotoxic to the tumor cells, even when obtained from tumor-immune rats. However, CD4(+) and CD8(+) T cells prepared from the regressing tumors induce tumoricidal activity in splenic macrophages from normal or tumor-bearing rats and in macrophages that infiltrate progressive tumors. These results strongly suggest that the main tumoricidal effector cells in preimmunized rats are macrophages that have been activated by adjacent tumor-immune lymphocytes.
T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. In human transplants, we show that donor-versus-recipient natural killer (NK)-cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD. In mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GVHD. NK cell alloreactivity may thus provide a powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.
Systemic treatment with antibody to CD40 ligand (aCD40L) can prevent autoimmunity and transplant rejection in several animal models and is currently under evaluation in clinical trials. While it is known that aCD40L administration inhibits expansion and effector functions of aggressive T cells, it is still unclear whether additional regulatory mechanisms are operative. Here we demonstrate that a single episode of CD40L blockade during development of the autoaggressive immune response completely prevented autoimmune disease in the RIP-LCMV mouse model for virally induced type 1 diabetes. Interestingly, protection could be transferred by a highly potent, bitypic cell population sharing phenotypic and functional properties of both natural killer (NK) and dendritic cells (DC). Furthermore, protection of prediabetic recipients was autoantigen specific and did not result in generalized immunosuppression. The origin, function, and therapeutic potential of these bitypic NK/DC regulatory cells is discussed.
Two functionally distinct subsets of B cells that produce Th1- and Th2-like patterns of cytokines have recently been identified. Interleukin-12 (IL-12) is a critical immunoregulatory cytokine that promotes Th1 differentiation through activation of signal transducer and activator of transcription 4 (STAT4). IL-12 has been reported to induce interferon gamma (IFN-gamma) production in B cells, but the relevant signaling pathways are poorly documented. Here, in human primary B cells, we found a functional IL-12 receptor (IL-12R) that internalizes following IL-12 binding. IFN-gamma and, to a lesser extent, IL-12 positively regulated the IL-12Rbeta2 subunit but had no effect on IL-12Rbeta1. On examining the effect of IL-12 on STAT4 and T-bet (2 key factors involved in IFN-gamma promoter activation), we found that IL-12 induced the phosphorylation and nuclear translocation of STAT4. IL-12-dependent constitutive STAT4 activation was also observed in the Epstein-Barr virus (EBV)-transformed B-cell line RPMI 8866 that spontaneously produces IL-12. T-bet expression has been shown to be dependent on STAT1. IL-12 had no direct effect on STAT1 activation or T-bet expression in primary B cells. In contrast, IL-12-induced IFN-gamma led to STAT1 activation, strong expression of T-bet, and IFN-gamma expression. IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rbeta2 up-regulation, IFN-gamma production, and T-bet up-regulation, potentially leading to Th1-like differentiation.
Plasmacytoid dendritic cells (PDCs) are crucial effectors in innate immunity. In this study, we show that imatinib, a potent inhibitor of BCR/ABL tyrosine kinase activity, in the presence of Flt3-Ligand, could induce CD34+ progenitors from chronic myeloid leukemia (CML) to give rise in vitro to typical BDCA-2+ type I interferon-producing PDCs. The effect of imatinib on PDC generation was related to up-regulation of Flt3 on leukemic CD34+ progenitors. Moreover, patients with chronic myeloid leukemia (CML) who were in complete cytogenetic or molecular response after imatinib treatment restored their blood PDCs both quantitatively and functionally comparable to healthy donors, in contrast to patients not responding to imatinib, further confirming that disease response to imatinib is accompanied by restoration of PDC function in vivo. These findings provide evidence that response to imatinib is capable to restore some DC-related immune functions in CML that might be beneficial for long-term disease control.
Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
Tumor antigen-specific T-cell tolerance imposes a significant barrier to the development of effective therapeutic cancer vaccines. Bone marrow-derived antigen-presenting cells (APCs) are critical in the induction of this unresponsive state. Here we show that in vitro treatment of APCs with the tyrosine kinase inhibitor, imatinib mesylate (STI-571), enhances the activation of naive antigen-specific T cells and restores the responsiveness of tolerant T cells from tumor-bearing hosts. Furthermore, in vivo treatment with STI-571 not only prevented the induction of tolerance in tumor-specific CD4(+) T cells, preserving their responsiveness to a subsequent immunization, but also resulted in enhanced vaccine efficacy. These findings demonstrate that tolerance to tumor antigens is not an insurmountable obstacle and points to modulation of APC function as a promising strategy in the immunotherapy of cancer.
Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor; however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D-NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor-related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.
Plasmacytoid dendritic cells (pDCs) competent to make type I interferon were rigorously defined as a Ly-6C(+) and CD11c(Lo) subset of the B220(+)CD19(-) CD43(+)CD24(Lo) bone marrow (BM) Fraction A. Otherwise similar Ly6C(-) cells expressed the natural killer (NK) markers DX5 and NK1.1. pDCs represented a stable, discrete, and long-lived population. Stem cells and early lymphoid progenitors (ELPs), but not prolymphocytes, were effective precursors of pDCs, and their differentiation was blocked by ligation of Notch receptors. Furthermore, pDCs were present in the BM of RAG1(-/-), CD127/IL-7Ra(-/-), and Pax5(-/-) mice. pDCs in RAG1/GFP knock-in mice could be subdivided, and immunoglobulin D(H)-J(H) rearrangements, as well as transcripts for the B-lineage-related genes Pax5, mb1/CD79a, ebf, and Bcl11a, were identified only in the green fluorescent protein-positive (GFP(+)) pDC1 subset. All pDCs expressed terminal deoxynucleotidyl transferase (TdT), the ETS transcription factor Spi-B, the nuclear factor-kappaB transcription factor RelB, toll-like receptor 9 (TLR9), and interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) transcripts; lacked CD16 and granulocyte colony-stimulating factor receptor (G-CSFR); and were uniformly interleukin-7 receptor alpha (IL-7Ralpha(-)) AA4.1(Lo), CD27(-), Flk-2(Lo), c-Kit(-), DX-5(-), and CD11b(-), while CD4 and CD8alpha were variable. GFP(+) pDC1 subset was less potent than GFP(-) pDC2s in T allostimulation and production of tumor necrosis factor alpha (TNFalpha), interferon alpha (IFNalpha), and interleukin-6 (IL-6), while only pDC2s made IFNgamma and IL-12 p70. Thus, 2 functionally specialized subsets of pDCs arise in bone marrow from progenitors that diverge from B, T, and NK lineages at an early stage.
Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-gamma, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.
Beta 2-Microglobulin-deficient (beta 2m -/-) mice are reported to lack cell surface expression of major histocompatibility complex (MHC) class I molecules, CD8+ T cells, and the ability to mount MHC class I-specific T cell responses. We have observed that beta 2m -/- mice possess CD8+ T cells that can be induced to perform strong allospecific cytotoxic responses against nonself-MHC class I by in vivo priming. We report that these beta 2m -/- cytotoxic T lymphocyte (CTL) differ from those induced in beta 2m-positive littermates in that they cross-react and kill cells expressing self-MHC class I at normal ligand density with beta 2m. beta 2m -/- CTL could even be induced in primary mixed lymphocyte culture by self-MHC class I expressing stimulator cells, whereas allogeneic stimulator cells failed to elicit a response under similar conditions. Cells with a reduced cell surface MHC class I expression were less sensitive, while syngeneic beta 2m -/- cells were resistant to the beta 2m -/- CTL. This antiself-MHC reactivity could not be induced when beta 2m -/- T cells matured in an environment with normal MHC class I expression in bone marrow chimeric mice. Antiself-MHC reactivity was also observed against human peptide loading-deficient cells expressing the appropriate murine class I molecules, suggesting that affinity to self-MHC class I may occur irrespective of peptide content. The results fit with a model where positive and negative selection of CD8+ T cells in beta 2m -/- mice is mediated by low levels of MHC class I free heavy chains. In this model, low ligand density on selecting cells leads to positive selection of rare T cells that bind to low levels of MHC class I free heavy chains, resulting in a very small peripheral CD8+ compartment. Due to low density of the selecting ligand, negative selection does not remove T cells recognizing beta 2m-positive cells expressing self-MHC class I at normal ligand density, which generates a T cell repertoire that would be autoreactive in a beta 2m-positive littermate. The first "MHC deficient" animals thus paradoxically provide a tool for direct demonstration and analysis of self MHC bias in the T cell repertoire.
Lymphocytes were originally thought to form the basis of a `cancer
immunosurveillance' process that protects immunocompetent hosts against
primary tumour development, but this idea was largely abandoned when no
differences in primary tumour development were found between athymic
nude mice and syngeneic wild-type mice. However, subsequent observations
that nude mice do not completely lack functional T cells and that two
components of the immune system-IFNγ and perforin-help to prevent
tumour formation in mice have led to renewed interest in a
tumour-suppressor role for the immune response. Here we show that
lymphocytes and IFNγ collaborate to protect against development of
carcinogen-induced sarcomas and spontaneous epithelial carcinomas and
also to select for tumour cells with reduced immunogenicity. The immune
response thus functions as an effective extrinsic tumour-suppressor
system. However, this process also leads to the immunoselection of
tumour cells that are more capable of surviving in an immunocompetent
host, which explains the apparent paradox of tumour formation in
immunologically intact individuals.
TRAIL induces apoptosis through two closely related receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Here we show that TRAIL-R1 can associate with TRAIL-R2, suggesting that TRAIL may signal through heteroreceptor signaling complexes. Both TRAIL receptors bind the adaptor molecules FADD and TRADD, and both death signals are interrupted by a dominant negative form of FADD and by the FLICE-inhibitory protein FLIP. The recruitment of TRADD may explain the potent activation of NF-κB observed by TRAIL receptors. Thus, TRAIL receptors can signal both death and gene transcription, functions reminiscent of those of TNFR1 and TRAMP, two other members of the death receptor family.
We demonstrated the induction of cell death in a hepatoma cell line by IFN- and its possible mechanism. Among the 2 hepatitis B virus (HBV)–associated hepatoma cell lines, SNU-354 and SNU-368, IFN- induced cell death and increased caspase-3 activity in SNU-368 but not in SNU-354. IFN- induced several changes in the mRNA expression level of apoptosis-regulating genes, e.g., increased expression of Fas, caspase-1 and TNF-related apoptosis-inducing ligand (TRAIL). In particular, IFN- potently increased the mRNA expression of TRAIL in both cell lines. However, it did not change the mRNA expression level of death-mediating TRAIL receptors, e.g., DR4 and DR5, which were constitutively expressed in both cell lines. In contrast, the decoy receptor DcR1 was expressed in SNU-354 but not in SNU-368, and its expression level in SNU-354 was increased by IFN-. Another decoy receptor, DcR2, was constitutively expressed in both cell lines; however, its expression level in SNU-368 was decreased by IFN-. In addition, exogenous recombinant TRAIL reduced viability in SNU-368, but not in SNU-354, cells. From these findings, we speculated that TRAIL up-regulation and the subsequent TRAIL-mediated apoptosis serve as a mechanism of IFN-–induced cell death in SNU-368. To confirm this hypothesis, we demonstrated that soluble DR4-Fc fusion protein, a TRAIL pathway inhibitor, inhibited IFN-–induced cell death in SNU-368. Our results demonstrated that IFN- acts as an inducer of cell death through TRAIL-mediated apoptosis. © 2001 Wiley-Liss, Inc.
Cowpox virus effectively inhibits inflammatory responses against viral infection in the chick embryo. This study demonstrates that one of the viral genes necessary for this inhibition, the crmA gene (a cytokine response modifier gene), encodes a serpin that is a specific inhibitor of the interleukin-1 beta converting enzyme. This serpin can prevent the proteolytic activation of interleukin-1 beta, thereby suppressing an interleukin-1 beta response to infection. However, the modification of this single cytokine response is not sufficient to inhibit inflammatory responses. This suggests that cowpox virus encodes several cytokine response modifiers that act together to inhibit the release of pro-inflammatory cytokines in response to infection. These viral countermeasures to host defenses against infection may contribute significantly to the pathology associated with poxvirus infections.
This study demonstrates that endogenously produced interferon gamma (IFN-gamma) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. Compared with wild-type mice, mice lacking sensitivity to either IFN-gamma (i.e., IFN-gamma receptor-deficient mice) or all IFN family members (i.e., Stat1-deficient mice) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen methylcholanthrene. In addition, IFN-gamma-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene. IFN-gamma-insensitive p53(-/-) mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. Using tumor cells derived from methylcholanthrene-treated IFN-gamma-insensitive mice, we found IFN-gamma's actions to be mediated at least partly through its direct effects on the tumor cell leading to enhanced tumor cell immunogenicity. The importance and generality of this system is evidenced by the finding that certain types of human tumors become selectively unresponsive to IFN-gamma. Thus, IFN-gamma forms the basis of an extrinsic tumor-suppressor mechanism in immunocompetent hosts.
Dendritic cells (DC) not only stimulate T cells effectively but are also producers of cytokines that have important immune regulatory functions. In this study we have extended information on the functional differences between DC subpopulations to include differences in the production of the major immune-directing cytokines IL-12, IFN-alpha, and IFN-gamma. Splenic CD4(-)8(+) DC were identified as the major IL-12 producers in response to microbiological or T cell stimuli when compared with splenic CD4(-)8(-) or CD4(+)8(-) DC; however, all three subsets of DC showed similar IL-12 regulation and responded with increased IL-12 p70 production if IL-4 was present during stimulation. High level CD8 expression also correlated with extent of IL-12 production for DC isolated from thymus and lymph nodes. By using gene knockout mice we ruled out any role for CD8alpha itself, or of priming by T cells, on the superior IL-12-producing capacity of the CD8(+) DC. Additionally, CD8(+) DC were identified as the major producers of IFN-alpha compared with the two CD8(-) DC subsets, a finding that suggests similarity to the human plasmacytoid DC lineage. In contrast, the CD4(-)8(-) DC produced much more IFN-gamma than the CD4(-)8(+) or the CD4(+)8(-) DC under all conditions tested.
Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice. However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response. Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals.
The TNF-related apoptosis-inducing ligand (TRAIL) offers great promise as a cancer therapeutic. Initially, soluble recombinant versions of the TRAIL molecule have exhibited specific tumoricidal activity against a variety of tumors alone, or in combination with other cancer treatments, and much anticipation awaits the outcomes from early clinical trials. More recently, the natural role of TRAIL has been explored in tumor and allogeneic bone marrow transplantation models in the mouse. Strikingly, the TRAIL effector pathway appears a vital component of immunosurveillance of spontaneous or resident tumor cells by both T cells and NK cells, stimulating more hope that manipulating TRAIL activity is a natural path to improved cancer immunotherapy.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells. Preclinical studies in mice and non-human primates have shown the potential utility of recombinant soluble TRAIL and agonistic anti-DR5 or DR4 antibodies for cancer therapy. Moreover, we have recently revealed a vital role for endogenously expressed TRAIL in immunosurveillance of developing and metastatic tumors. In this review, we summarize recent knowledge about TRAIL and its receptors as promising targets for cancer therapy.
This work was also supported by EU grants
- Inserm Accueil
- Dc Allostem
- Thera
Accueil INSERM. This work was also supported by EU grants (ALLOSTEM, DC THERA), ARC and the Ligue Nationale contre le Cancer (e ´quipes labelisé de G.K. and L.Z).
IFN producing Killer-dendritic cells directly link innate and adaptative immunity
- C W Chan
Chan, C.W. et al. IFN producing Killer-dendritic cells directly link innate and adaptative immunity. Nat. Med. (in the press).
Demonstration of an IFNγ-dependent tumor surveillance system in immunocompetent mice
- D H Kaplan
- DH Kaplan