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Flow cytometric analysis of CD8+ and CD4+ cells. (A) Effects of CD200fc treatment on tumor infiltrating CD8+ cells.
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CD200 is a widely expressed cell surface glycoprotein that inhibits excessive inflammation in autoimmunity, transplantation, and viral infections. We previously observed that visceral metastasis of highly aggressive and inflammatory 4THM breast carcinoma cells was markedly decreased in CD200 transgenic mice. The goal of this study was to determine...
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... Additionally, we examined the impact of quetiapine on certain aspects of inflammatory processes, including selected markers of the pro-and anti-inflammatory profile of microglial activity (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β) and cytokine release (IL-6, IL-10). In the final stage of our research, we introduced a soluble CD200 fusion protein containing the ectodomain of CD200 bound to a murine IgG2a module (CD200Fc), which mimics the effects of the ligand CD200 [25,26], to determine whether the modulation of CD200R could influence the IL-6 and IL-10 protein levels. ...
Atypical antipsychotics currently constitute the first-line medication for schizophrenia, with quetiapine being one of the most commonly prescribed representatives of the group. Along with its specific affinity for multiple receptors, this compound exerts other biological characteristics, among which anti-inflammatory effects are strongly suggested. Simultaneously, published data indicated that inflammation and microglial activation could be diminished by stimulation of the CD200 receptor (CD200R), which takes place by binding to its ligand (CD200) or soluble CD200 fusion protein (CD200Fc). Therefore, in the present study, we sought to evaluate whether quetiapine could affect certain aspects of microglial activity, including the CD200-CD200R and CX3CL1-CX3CR1 axes, which are involved in the regulation of neuron–microglia interactions, as well as the expression of selected markers of the pro- and anti-inflammatory profile of microglia (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β). Concurrently, we examined the impact of quetiapine and CD200Fc on the IL-6 and IL-10 protein levels. The abovementioned aspects were investigated in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those subjected to maternal immune activation (MIA OCCs), which is a widely implemented approach to explore schizophrenia-like disturbances in animals. The experiments were performed under basal conditions and after additional exposure to the bacterial endotoxin lipopolysaccharide (LPS), according to the “two-hit” hypothesis of schizophrenia. The results of our research revealed differences between control and MIA OCCs under basal conditions and in response to treatment with LPS in terms of lactate dehydrogenase and nitric oxide release as well as Cd200r, Il-1β, Il-6 and Cd206 expression. The additional stimulation with the bacterial endotoxin resulted in a notable change in the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Quetiapine diminished the influence of LPS on Il-1β, Il-6, Cebpb and Arg1 expression in control OCCs as well as on IL-6 and IL-10 levels in MIA OCCs. Moreover, CD200Fc reduced the impact of the bacterial endotoxin on IL-6 production in MIA OCCs. Thus, our results demonstrated that quetiapine, as well as the stimulation of CD200R by CD200Fc, beneficially affected LPS-induced neuroimmunological changes, including microglia-related activation.
... In preliminary studies, growth of tumor in this model was attenuated using therapy with anti-CD200mAb and was associated with augmented host anti-tumor immunity [94]. Interestingly, use of CD200fc, which is an CD200R1 agonist, significantly decreased the growth of metastatic breast cancer 4THM cells due to the inhibition of cancer-related inflammation and increase both the tumor-infiltrating CD8+ T cell number and tumor-induced IFN-γ secretion [95]. ...
The molecule CD200, described many years ago as a naturally occurring immunomodulatory agent, capable of regulating inflammation and transplant rejection, has attracted additional interest over the past years with the realization that it may also serve as an important marker for progressive malignancy. A large body of evidence also supports the hypothesis that this molecule can contribute to immunoregulation of, among other diseases, infection, autoimmune disease and allergy. New data have also come to light to characterize the receptors for CD200 (CD200R) and their potential mechanism(s) of action at the biochemical level, as well as the description of a novel natural antagonist of CD200, lacking the NH2-terminal region of the full-length molecule. Significant controversies exist concerning the relative importance of CD200 as a ligand for all reported CD200Rs. Nevertheless, some progress has been made in the identification of the structural constraints determining the interaction between CD200 and CD200R, and this information has in turn proved of use in developing novel small molecule agonists/antagonists of the interaction. The review below highlights many of these newer findings, and attempts to place them in the broad context of our understanding of the role of CD200-CD200R interactions in a variety of human diseases.
... Under certain conditions, however, activation of NK1R might induce anti-inflammatory immune response which may increase cytotoxic immunity [26,39]. Recent studies documented that concentration and structure of NK1R determines the type of immune response elicited by SP [17,27,40,41]. ...
Substance P a neuro-immune mediator acts on Neurokinin-1 and -2 receptors (NK1R and NK2R). Inhibitors of NK1R are considered to be safe and effective approaches for cancer treatment since Aprepitant, a non-peptide antagonist of NK1R is widely used for chemotherapy-induced emesis and has cytotoxic and antitumor effects in various models for cancer. On the other hand, our previous findings demonstrated that systemic inhibition of NK1R may decrease cytotoxic anti-tumoral immune response. Hence, actual consequences of inhibition of neurokinin receptors under in vivo conditions in a syngeneic model of carcinoma should be determined. The effects of highly potent and selective non-peptide mouse NK1R and NK2R antagonists RP 67580 and GR 159897, respectively, on metastatic breast carcinoma were evaluated. Specifically, 4T1 breast cancer cells metastasized to brain (denoted as 4TBM) and liver (denoted as 4TLM) were used to induce tumors in Balb-c mice. Changes in tumor growth, metastasis and immune response to cancer cells were determined. We here observed differential effects of NK1R antagonist depended on the subset of metastatic cells. Specifically, inhibition of NK1R markedly increased liver metastasis of tumors formed by 4TBM but not 4TLM cells. On the contrary, NK1R antagonist decreased inflammatory response and liver metastasis in 4TLM-injected mice. 4TLM tumors act more aggressively inducing more inflammatory response compared to 4TBM tumors. Hence, differential effects of NK1R antagonist are at least partly due to extend and type of the inflammatory response evoked by specific subset metastatic cells. These findings demonstrate the necessity for understanding the immunological consequences of tumor-microenvironment interactions.
... Several potential mechanisms have been associated with CD200R1 and immune responses [17,20,22]. For instance, 4THM breast cancer cell growth and invasion were increased in CR200R1KO mice and decreased in mice over-expressing CD200, with a lack of CD200R1 expression related to decreased CD8 + and CD3 + CD25 + T cells [23]. ...
... In contrast, CD200 overexpression in CD200 transgenic mice was found to increase tumor-induced IFN-γ and decrease inflammatory cytokine, TNF-α, and IL-6 expression. Moreover, CD200fc, which mimics the effect of CD200, significantly decreased tumor growth and metastasis in a mouse model of breast cancer, increased IFN-γ and decreased IL-6 expression, and time-dependently altered IL-10 and IL-17 levels [22]. In this study, we analyzed genes that are biologically related to CD200R1 using the STRING database and by conducting a literature review. ...
... Collectively the associations between CD200R1 and these diverse immune-related proteins suggest that CD200R1 is involved in a variety of immune mechanisms and may explain why HNSCC with high CD200R1 expression is related to an 'immune-rich' microenvironment with high immune cell estimates. Thus, our findings suggest that modulation of the CD200R1 pathway could be used as an immunotherapeutic strategy in patients with HNSCC [22,35,36]. ...
Immune system dysfunction is associated with head and neck squamous cell carcinoma (HNSCC) development and progression and immune checkpoint inhibitors have demonstrated substantial survival benefits in platinum-refractory HNSCC; therefore, we examined the prognostic value of immune-related gene (IRG) expression in HNSCC. We analyzed the expression of 82 IRGs in 71 patients with HNSCC enrolled in a feasibility study for a prospective HNSCC biomarker-driven umbrella trial (Korean Cancer Study Group TRIUMPH study, NCT03292250). CD200R1 was identified as an independent prognostic factor and validated in GEO and TCGA database. CD2000R1 mRNA expression was found to be an independent favorable prognostic factor in patients with HNSCC. Moreover, CD200R1 was found to affect genes and pathways associated with the immune response, while seven differentially expressed genes (CD8A, DOK2, CX3CR1, TYROBP, CXCL9, CD300LF, IFNG) were associated with CD200R1 expression. Samples with higher CD200R1 expression displayed higher tumor-infiltrating immune cell counts both in silico and in histological analysis. These findings will help in the development of more accurate prognostic tools and suggest CD200R1 modulation as a HNSCC immunotherapy.
... There is mounting evidence demonstrating a significant role of factors originating from the tumor microenviroment (TME) for both responsiveness or resistance to various structurally and mechanistically unrelated anticancer drugs. The persistent production of inflammatory factors has been reported in TME-mediated EMT, metastasis and chemotherapy resistance (Acharyya et al., 2012;Bunt et al., 2006;Hartmann et al., 2005;Gao et al., 2020;Krchniakova et al., 2020;Shaked, 2019;Erin et al., 2015Erin et al., , 2018aErin et al., , 2018bErin et al., , 2020Nizam et al., 2020). This may be due to inflammation-induced expansion and recruitment of macrophages and CD11b + /Gr-1 + myeloid-derived suppressor cells (MDSCs) (Szebeni et al., 2017;Xu et al., 2017) as well cancer-associated fibroblasts (CAFs) (Bharti et al., 2016). ...
... N. Erin, et al. Drug Resistance Updates 53 (2020) 100715 et al., 2019), which may have been responsible for the suppression of MDSCs, since inhibition of inflammation using CD200 mimetics also decreased MDSCs (Erin et al., 2015(Erin et al., , 2018b and increased the therapeutic potential of doxorubicin . Inhibition of mTOR activity with everolimus is a relatively new therapeutic approach for various carcinomas, including breast, prostate, neuroendocrine tumors and renal cell carcinoma (Deniz et al., 2019;George et al., 2019;Huijts et al., 2019;Larouche et al., 2019;Schmid et al., 2019;Wen et al., 2019). ...
It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) is crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurture tumor-initiating/cancer stem-like cells (CSCs) induce both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR.
Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.
... Perineuronal stimulation also activates vagal efferent pathways. Activation of vagal efferents increases cholinergic parasympathetic activity and the cholinergic anti-inflammatory pathway which may also prevent inflammation-related metastasis as demonstrated in our models [31][32][33]. On the other hand, this approach may not be suitable for all types of cancer and modifications might be required since increased parasympathetic cholinergic fibers were shown to promote prostate cancer invasion Fig. 1 Effects of perineural capsaicin treatment of vagus nerve on breast cancer metastasis. ...
Sensory nerves sensitive to capsaicin are afferent nerve fibers which contain TRPV1 channels. Activation of these channels induces release of neuropeptides which regulate local blood flow and immune response. Inactivation of sensory neurons either with high-dose capsaicin treatment or local ablation of vagal sensory nerve activity markedly increases metastasis of breast carcinoma formed by 4T1 derivative cells. These cancer cells also induce an extensive systemic inflammatory response. Further findings have documented that lack of local sensory neuromediators alters phenotype of cancer cells within primary tumor leading to overgrowth of metastatic subsets. This might be due to decreases in local and systemic immune response to growing tumor. Specifically, Substance P, one of the most abundant sensory neuropeptides, enhances anti-tumoral immune response evoked by radiotherapy under in vivo conditions. These findings further suggest that activation of TRPV1 channels on sensory neurons may induce an anti-tumoral immune response. We are testing this hypothesis. Our initial results as reported here demonstrate anti-inflammatory consequences of low-dose systemic capsaicin treatment. In conclusion, sensory nerve fibers sensitive to capsaicin have important roles in defense against metastatic breast carcinoma; hence, controlled activation of these neural pathways might be effective in cancer therapy. Specifically, activation of sensory fibers of left vagus nerve using a perineuronal stimulation may inhibit metastasis of breast carcinoma. Likewise, pharmacological modulators of TRPV1 channels may induce anti-tumoral immune response. Exact players of this newly explored defense system are, however, only partly validated, and further studies are required.
... CD200 overexpression increased the anti-tumoral immune response and inhibited excessive inflammation in 4THM breast carcinoma [4]. Similarly, we also reported that a soluble CD200 fusion protein, containing the ectodomain of CD200 bound to a murine IgG2a module (CD200Fc) [5], markedly decreased lung and liver metastasis and the growth of breast carcinoma [6]. Although it is thought that CD200 functions primarily through a CD200 receptor 1(CD200R1), which is expressed mostly by myeloid cells and some subsets of lymphoid-derived cells [1,7], several functions of CD200 might be mediated by receptors other than CD200R1 [8,9]. ...
... Because overexpression of CD200 as well as CD200Fc both increased anti-tumoral immunity against aggressive breast carcinoma [4,6], we hypothesized that molecular mimetics of CD200 and doxorubicin would act synergistically to produce anti-tumoral effects. A 4THM tumor model was used to investigate this possibility. ...
... 4THM cells (1 × 10 4 cells per mouse) were injected orthotopically into the right upper mammary gland of 8-10-week female recipients. In our previous publications, we used 1 × 10 5 cells per mouse [4,6]. In these studies, we decreased the initial cell numbers to allow time for a micro-environmental response to develop. ...
We previously reported that CD200 overexpression in the host decreases progression and metastasis of the highly aggressive metastatic 4THM breast carcinoma. We have explored a possible synergistic interaction between the CD200 mimetic PEG-M49 and pegylated liposomal doxorubicin (Peg-Dox) in wild-type CD200 knockout (CD200-/-) and CD200 Receptor 1 knockout (CD200R1-/-) mice for the first time. A 4THM breast carcinoma model and three groups of BALB/c mice (wild type, CD200-/- and CD200R1-/-) were used. Five days after injection of tumor cells, mice were injected with Peg-Dox (ip, once a week) and PEG-M49 or a control aptamer (iv, every 3 days). Necropsies were performed either 12 (mid-point) or 24 (endpoint) days after injection and the extent of tumor growth, visceral metastasis and changes in the tumor-directed immune response were evaluated. PEG-M49 and Peg-Dox co-treatment induced complete tumor regression and loss of macroscopic lung metastasis in four out of seven WT mice. This synergistic anti-tumoral effect is thought to be due to Peg-M49-induced inhibition of Gr1 + CD11b + cells and Peg-Dox-induced increases in tumor-infiltrating CD8 + and CD8CD4 double-positive cells. Similar changes were observed in CD200R1-/- mice indicating that the primary effects of Peg-M49 are mediated by non-CD200R1 receptors. We also demonstrated for the first time that tumor growth, metastasis, and tumor infiltrating GR1 + CD11b + cells were markedly increased in CD200R1-/- mice, indicating an anti-inflammatory and protective role of CD200. CD200 mimetics might be a safe and effective immunomodulatory treatment in conjunction with classical chemotherapeutics for therapy of aggressive metastatic breast carcinoma.
... Cancer cells can create an inflammatory microenvironment to enhance the tumor metastatic process (32). It is reported that excessive and chronic activation of the immune system is involved in breast cancer metastasis (33). TNF alpha induced protein 6 (TNFAIP6) encodes inflammatory response factors and regulates anti-inflammation response and immunosuppression (34,35). ...
... In addition, it has been demonstrated that the enhancement of the CD200-CD200 receptor interaction inhibits the metastasis of breast cancer (43). It is reported that CD200 analogs may have therapeutic potential in treating aggressive breast carcinoma (33). ASS1 (44) and VIM (45) are both prognostic indicators in breast cancer patients. ...
Background: Bone metastasis frequently occurs in advanced breast cancer patients, and it is one of major causes of breast cancer associated mortality. The aim of the current study is to identify potential genes and related signaling pathways in the pathophysiology of breast cancer bone metastasis.
Methods: Three mRNA expression datasets for breast cancer bone metastasis were obtained from Gene Expression Omnibus (GEO) dataset. The differentially expressed genes (DEGs) were obtained. Functional analyses, protein-protein interaction (PPI) network, and transcription factors (TFs)-target genes network was constructed. Real-time PCR using clinical specimens was conducted to justify the results from integrated analysis.
Results: A 749 DEGs were obtained. Osteoclast differentiation and rheumatoid arthritis were two significantly enriched signaling pathways for DEGs in the bone metastasis of breast cancer. SMAD7 (degree = 10), TGFBR2 (degree = 9), VIM (degree = 8), FOS (degree = 8), PDGFRB (degree = 7), COL5A1 (degree = 6), ARRB2 (degree = 6), and ITGAV (degree = 6) were high degree genes in the PPI network. ETS1 (degree = 12), SPI1 (degree = 12), FOS (degree = 10), FLI1 (degree = 5), KLF4 (degree = 4), JUNB (degree = 4), NR3C1 (degree = 4) were high degree genes in the TFs-target genes network. Validated by QRT-PCR, the expression levels of IBSP, MMP9, MMP13, TNFAIP6, CD200, DHRS3, ASS1, RIPK4, VIM, and PROM1 were roughly consistent with our integrated analysis. Except PROM1, the other genes had a diagnose value for breast cancer bone metastasis.
Conclusions: The identified DEGs and signaling pathways may make contribution for understanding the pathological mechanism of bone metastasis from breast cancer.
CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)–induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP. Upon pretreatment of cells with increasing concentrations of IFN-α, CD200R switched from inhibiting to potentiating the TLR7- and TLR8-induced expression of the gene encoding IFN-γ, a cytokine that is important for innate and adaptive immunity and is implicated in systemic lupus erythematosus (SLE) pathogenesis. PBMC from patients with SLE, a prototypic type I IFN disease, had an increased abundance of cleaved p120-RasGAP compared to that in cells from healthy controls. In a subset of SLE patients, CD200R stopped functioning as an inhibitory receptor or potentiated TLR-induced IFNG mRNA expression. Thus, our data suggest that type I IFN rewires CD200R signaling to be proinflammatory, which could contribute to the perpetuation of inflammation in patients with SLE.
