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Tumor Volume and Survival Curves after Treatment in the Two Tumor Mouse Model. To investigate whether aFP treatment could induce systemic anti-tumor immunity, we established a mouse model which has one tumor on each hind leg with the aFP-treated tumor on the left leg and observed the growth of both tumors. aFP laser irradiation was performed 7 days after tumor inoculation. Anti-PD-1 blocking antibodies were administered intraperitoneally at a dose of 200 µg per mouse on days 7, 9, 11, 13, and 15 after tumor cell inoculation. (a) Average of tumor volume curves on the treated legs of mice in the control, anti-PD-1, aFP and aFP + anti-PD-1 groups after tumor inoculation. (b) Average of tumor volume curves on the untreated contralateral legs of mice in the control, anti-PD-1, aFP and aFP + anti-PD-1 groups after tumor inoculation. (c) Individual tumor volume curves in the control, anti-PD-1, aFP and aFP + anti-PD-1 groups after tumor inoculation. (d) Kaplan-Meier survival curves of mice receiving tumor inoculation. The significance values for the difference between the survival curves are: Control vs. aFP + anti-PD1: P < 0.005, Anti-PD-1 vs. aFP + anti-PD1: P < 0.005, aFP vs. aFP + anti-PD1: P < 0.01. The bars represent SD. *P < 0.05, **P < 0.01, ***P < 0.005.
Source publication
Currently ablative fractional photothermolysis (aFP) with CO2 laser is used for a wide variety of dermatological indications. This study presents and discusses the utility of aFP for treating oncological indications. We used a fractional CO2 laser and anti-PD-1 inhibitor to treat a tumor established unilaterally by the CT26 wild type (CT26WT) colon...
Contexts in source publication
Context 1
... we established a two tumor mouse model, which has a tumor on both hind legs, with the aFP-treated tumor on the left leg and observed the growth of both tumors. aFP laser irradiation was performed 7 days after tumor inoculation. The aFP significantly led to a reduction in tumor volume and growth rate of aFP-treated tumors after the treatment (Fig. 4a and c). Regarding the untreated contralateral tumors, we found that the aFP + anti-PD-1 combination therapy led to a significant reduction in growth rate after the treatment (Fig. 4b and c). Moreover the untreated contralateral tumors shrank in 2 of the 6 mice in the aFP + anti-PD-1 group completely, but such shrinkage did not occur in the ...
Context 2
... was performed 7 days after tumor inoculation. The aFP significantly led to a reduction in tumor volume and growth rate of aFP-treated tumors after the treatment (Fig. 4a and c). Regarding the untreated contralateral tumors, we found that the aFP + anti-PD-1 combination therapy led to a significant reduction in growth rate after the treatment (Fig. 4b and c). Moreover the untreated contralateral tumors shrank in 2 of the 6 mice in the aFP + anti-PD-1 group completely, but such shrinkage did not occur in the rest of the groups ( Fig. 4c and d). The significance value for the difference between the survival curves are: control vs. aFP + anti-PD-1 (p < 0.005), anti-PD-1 vs. aFP + anti-PD-1 (p ...
Context 3
... the untreated contralateral tumors, we found that the aFP + anti-PD-1 combination therapy led to a significant reduction in growth rate after the treatment (Fig. 4b and c). Moreover the untreated contralateral tumors shrank in 2 of the 6 mice in the aFP + anti-PD-1 group completely, but such shrinkage did not occur in the rest of the groups ( Fig. 4c and d). The significance value for the difference between the survival curves are: control vs. aFP + anti-PD-1 (p < 0.005), anti-PD-1 vs. aFP + anti-PD-1 (p < 0.005), aFP vs. aFP + anti-PD-1 (p < 0.01). aFP induces recruitment of CD3+, CD4+, CD8+ and epitope specific CD8+ T lymphocytes but increases infiltration of Treg into the untreated ...
Citations
... Previous studies have shown that AFL treatment leads to many different tissue responses ranging from wound healing activation [8,9] and immune cell recruitment [10,11] to skin cancer prevention [12][13][14]. On a cellular level, these responses are associated with changes in expression levels of various genes [8,9,14]. ...
This study aimed to investigate the impact of ablative fractional laser (AFL) on hedgehog pathway gene expression in murine microscopic basal cell carcinomas (BCCs) and compare these results to the effect of topical treatment with vismodegib, an FDA-approved hedgehog inhibitor. In 25 mice, 1 cm² skin test sites (n = 44) containing microscopic BCCs were exposed to one of three interventions: a single CO2 AFL treatment (1 pulse, 40 mJ/microbeam, wavelength 10.6 μm, 5% density, pulse rate 250 Hz, n = 12), eight topical vismodegib treatments (3.8 mg/mL, n = 8), or combination of AFL and vismodegib treatments (n = 9). Untreated controls were included for comparison (n = 15). After 4 days, skin samples were analyzed for hedgehog gene expression (Gli1, Gli2, and Ptch1) by qPCR and vismodegib concentrations by liquid chromatography mass spectrometry (data analyzed with two-tailed t-tests and linear regression). A single treatment with AFL monotherapy significantly reduced hedgehog gene expression compared to untreated controls (Gli1 72.4% reduction, p = 0.003; Gli2 55.2%, p = 0.010; Ptch1 70.9%, p < 0.001). Vismodegib treatment also reduced hedgehog gene expression (Gli1 91.6%; Gli2 83.3%; Ptch1 83.0%), significantly surpassing AFL monotherapy for two out of three genes (Gli1, p = 0.017; Gli2, p = 0.007; Ptch1, p = 0.15). AFL and vismodegib combination mirrored the effects of vismodegib monotherapy (Gli1, p = 0.424; Gli2, p = 0.289; Ptch1, p = 0.593), possibly due to comparable cutaneous vismodegib concentrations (mean ± SD, vismodegib monotherapy 850 ± 475 µmol/L; combination 1036 ± 824 µmol/L; p = 0.573). In conclusion, a single AFL treatment significantly reduced hedgehog gene expression in murine BCCs mimicking the effects of eight topical applications of vismodegib. Further studies are needed to assess whether AFL can be utilized for BCC treatment, either as monotherapy or in combination with other drugs.
... While many physical interventions could serve as a stimulator of the immune systems, AFL was chosen in the current study for several reasons: AFL is well-established in dermatology with the advantage of producing standardized interventions, inducing a grid of microscopic zones of abalted tissue surrounded by the thermally coagulated tissue in the treated skin [18]. Partly due to this thermal injury, a substantial antitumor immune response is stimulated with the recruitment of neutrophils and cytotoxic T-cells [19], induction of immunogenic cell death, and activation of innate and adaptive immune cells [20][21][22]. Further, the concept of laser immunotherapy is gaining impact [23], with promising results in preclinical studies where AFL applied as an adjuvant to systemic anti-PD1 was superior to anti-PD1 alone in terms of overall survival, tumor growth, and immune cell attraction in mu-rine BCC models [8]. ...
... In pre-clinical trials, AFL-induced tumor-specific CD8+ T-cells have been shown [19]. In human BCC, tumor specific T-cell clones have not been found [24], and based on our results, AFL does not induce a CD8+ T-cell response in BCC, at least not in response to a single exposure. ...
The use of immune checkpoint inhibitors (ICI) is expanding with the approval for advanced/metastatic keratinocyte carcinoma; however, most tumors are non-aggressive. Local administration could broaden ICI, but adequate immune response might require an immune-attractive adjuvant such as ablative fractional laser (AFL). Accordingly, this study aimed to explore intratumoral injection of anti-PD1 with and without AFL in basal cell carcinoma (BCC), exploring anti-PD1 concentration, immune cell infiltration, tumor response, and safety. This open-label, proof-of-concept trial investigated intratumoral anti-PD1 + AFL combination therapy versus anti-PD1 or AFL monotherapy in 28 BCC patients. The primary endpoints were immune cell infiltration evaluated immunohistochemically and clinical tumor response after 3 months. The secondary outcomes were tumoral drug concentration and safety. The most robust response was obtained following intervention with combined anti-PD1+AFL, leading to a ~2.5-fold increase in CD3+ cells (p = 0.027), and tumor reduction ≥25% in 73%, including two tumors with complete remission. Upon anti-PD1 monotherapy, a slight decrease in CD3+ cells was observed while a non-significant increase following AFL was seen. Tumor reduction ≥25% was seen in 45% and 50%, respectively, after anti-PD1 and AFL monotherapy. The CD8/CD3 ratio remained unchanged after anti-PD1+AFL and anti-PD1 monotherapy, while AFL led to a decreased ratio. A non-significant decline in the Foxp3/CD3 ratio was observed for all groups. Side-effects were mild with no systemic drug concentration detected. Intratumoral anti-PD1 injection is feasible, and a single exposure to locally injected anti-PD1 with adjuvant AFL increased immune cell infiltration and reduction in BCC with limited side-effects.
... BALB/c mice (female, 6-8 weeks old and 18-20 g) were purchased from Changzhou Cavens Laboratory Animal Co., Ltd. and were maintained under a controlled temperature of 20-25 °C and relative humidity of 40 15:192 Establishment of the murine colon cancer model and infection with P. yoelii A colon cancer model was established as described by Kawakubo et al. [31]. Ten BALB/c mice were subcutaneously inoculated with 0.1 ml CT26.WT cell suspension (5 × 10 6 /ml) per mouse below the axilla of the right forelimb. ...
Background
Colon cancer is a common gastrointestinal tumor with a poor prognosis, and thus new therapeutic strategies are urgently needed. The antitumor effect of Plasmodium infection has been reported in some murine models, but it is not clear whether it has an anti-colon cancer effect. In this study, we investigated the anti-colon cancer effect of Plasmodium infection and its related mechanisms using a mouse model of colon cancer.
Methods
An experimental model was established by intraperitoneal injection of Plasmodium yoelii 17XNL-infected erythrocytes into mice with colon cancer. The size of tumors was observed dynamically in mice, and the expression of Ki67 detected by immunohistochemistry was used to analyze tumor cell proliferation. Apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, and the expression of apoptosis-related proteins including Bax, Bcl-2, caspase-9, and cleaved caspase-3 was detected by western blot and immunohistochemistry, respectively. Transmission electron microscopy (TEM) was used to observe the ultrastructural change in colon cancer cells, and the expression of mitochondrial biogenesis correlative central protein, PGC-1α, and mitophagy relevant crucial proteins, PINK1/Parkin, were detected by western blot.
Results
We found that Plasmodium infection reduced the weight and size of tumors and decreased the expression of Ki67 in colon cancer-bearing mice. Furthermore, Plasmodium infection promoted mitochondria-mediated apoptosis in colon cancer cells, as evidenced by the increased proportion of TUNEL-positive cells, the upregulated expression of Bax, caspase-9, and cleaved caspase-3 proteins, and the downregulated expression of Bcl-2 protein. In colon cancer cells, we found destroyed cell nuclei, swollen mitochondria, missing cristae, and a decreased number of autolysosomes. In addition, Plasmodium infection disturbed mitochondrial biogenesis and mitophagy through the reduced expression of PGC-1α, PINK1, and Parkin proteins in colon cancer cells.
Conclusions
Plasmodium infection can play an anti-colon cancer role in mice by inhibiting proliferation and promoting mitochondria-mediated apoptosis in colon cancer cells, which may relate to mitochondrial biogenesis and mitophagy.
Graphical Abstract
... Establishment of the murine colon cancer model and infection with the P. yoelii A colon cancer model was established as described Masayoshi [30]. As the subcutaneous model of colon cancer-bearing mice, ten BALB/c mice were established by subcutaneous inoculation of 5×10 6 CT26.WT cells below the axilla of the right forelimb in the mouse. ...
Background: Colon cancer is a common gastrointestinal tumor with a poor prognosis, which makes it urgent to explore new therapeutic strategies. The anti-tumor effect of Plasmodium infection has been reported in some murine models, but it is not clear whether it has an anti-colon cancer effect. In this study, we investigated the anti-colon cancer effect of Plasmodium infection and its related mechanisms using a mouse model of colon cancer.
Methods: An experimental model was established by intraperitoneal injection of Plasmodium yoelii-infected erythrocytes into mice with colon cancer. The size of tumors was observed dynamically in mice, and the expression of Ki67 detected by immunohistochemistry was to analyze tumor cells proliferation. Apoptosis was assessed by Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining, and the expression of apoptosis concerned proteins, including Bax, Bcl-2, Caspase-9, Cleaved Caspase-3, were detected by western blot and immunohistochemistry, respectively. Transmission electron microscopy (TEM) was used to observe the ultrastructural change of colon cancer cells. And the expression of mitochondrial biogenesis correlative central protein, PGC-1α, and mitophagy relevant crucial proteins, PINK1/Parkin, were detected by western blot.
Results: We found that Plasmodium infection reduced the weights and sizes of tumors and decreased the expression of Ki67 in colon cancer-bearing mice. Furthermore, Plasmodium infection promoted mitochondria-mediated apoptosis in colon cancer cells, as evidenced by the increased proportion of TUNEL-positive cells, the up-regulated expression of Bax, Caspase-9, and Cleaved Caspase-3 proteins, and the down-regulated expression of Bcl-2 protein. In colon cancer cells, we found destroyed nucleus, swollen mitochondria, missing cristae, and the decreased number of autolysosomes. In addition, Plasmodium infection disturbed mitochondrial biogenesis and mitophagy through the reduced expression of PGC-1α, PINK1, and Parkin proteins in colon cancer tissues.
Conclusions: Plasmodium infection can play an anti-colon cancer role in mice by inhibiting proliferation and promoting mitochondria-mediated apoptosis in colon cancer cells, which may relate to mitochondrial biogenesis and mitophagy.
... Ablative fractional laser (AFL) is a well-established modality in dermatology that induces a grid of microscopic treatment zones of ablated tissue that are surrounded by the thermally coagulated tissue in the treated skin [18]. AFL exposure, partially due to the thermal injury to skin cells, stimulates a substantial anti-tumor immune response, including recruitment of neutrophils and antigen-specific cytotoxic T-cells [10,19,20]. This process involves the induction of immunogenic cell death followed by the release of damage-associated molecular patterns (DAMPs) and potential neoantigens, resulting in the activation of innate and adaptive immune cells [21][22][23][24][25]. ...
... In accordance with this, AFL has been shown to stimulate the local infiltration of immune cells in healthy human skin by increasing the levels of immune-attracting cytokines and growth factors, including IL-6, transforming growth factor-β, basic fibroblast growth factor, and platelet-derived growth factor [26,27]. Further, in murine syngeneic tumor models (i.e., subcutaneousinoculated tumor models), AFL has been shown to induce tumor-specific cytotoxic T-cells and adaptive anti-tumor immunity [19,20]. Finally, AFL has been reported to boost the tumor response of immunotherapy, including aPD-1 [19,20,24] and the Toll-like receptor agonist imiquimod in preclinical studies [28]. ...
... Further, in murine syngeneic tumor models (i.e., subcutaneousinoculated tumor models), AFL has been shown to induce tumor-specific cytotoxic T-cells and adaptive anti-tumor immunity [19,20]. Finally, AFL has been reported to boost the tumor response of immunotherapy, including aPD-1 [19,20,24] and the Toll-like receptor agonist imiquimod in preclinical studies [28]. ...
The efficacy of anti-programmedcelldeath1therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC) treatment, can be enhanced by adjuvant ablative fractional laser (AFL) in syngeneic murine tumor models. In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant autochthonous BCC model. BCC tumors (n = 72) were induced in Ptch1+/−K14-CreER2p53fl/fl-mice (n = 34), and the mice subsequently received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. The outcome measures included mouse survival time, tumor clearance, tumor growth rates, and tumor immune infiltration. Both aPD-1 and AFL alone significantly increased survival time relative to untreated controls (31 d and 34.5 d, respectively vs. 14 d, p = 0.0348–0.0392). Complementing aPD-1 with AFL further promoted survival (60 d, p = 0.0198 vs. aPD-1) and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in the tumors. Similar to AFL alone, combined aPD-1 and AFL increased neutrophil counts (4-fold, p = 0.0242), the proportion of MHCII-positive neutrophils (p = 0.0121), and concordantly, CD4+ and CD8+ T-cell infiltration (p = 0.0061–0.0242). These descriptive results suggest that the anti-tumor response that is generated by aPD-1 with adjuvant AFL is potentially promoted by increased neutrophil and T-cell engraftment in tumors. In conclusion, local AFL shows substantial promise as an adjuvant to systemic aPD-1 therapy in a clinically relevant preclinical BCC model.
... After 48 h, increases in lymphocytes, altered T-reg vs CD8 ratios, increases in macrophages and growth factors are reported in a range of studies. Shown in mice, increased CD3, CD4 and CD8 + T-cell lymphocyte infiltration occurred in intradermally injected tumors of the thigh established by inoculation of a wild-type colon carcinoma cell line following AFL exposure [38]. Interestingly, AFL-induced tumor-specific CD8 + T-cell responses have been shown in two experiments [34,38]. ...
... Shown in mice, increased CD3, CD4 and CD8 + T-cell lymphocyte infiltration occurred in intradermally injected tumors of the thigh established by inoculation of a wild-type colon carcinoma cell line following AFL exposure [38]. Interestingly, AFL-induced tumor-specific CD8 + T-cell responses have been shown in two experiments [34,38]. The potential for laserinduced tumor-specific lymphocyte infiltration in at least some instances thus appears possible. ...
... Some studies point to an increased ratio of CD8 versus T-reg following AFL [34,38]. T-regs are recruited as a subpopulation of TILs and are generally considered suppressors of tumor-specific antigen-response. ...
The role of the immune system in cancer growth is well recognized and the development of immunotherapy represents a breakthrough in cancer treatment. Recently, the use of systemic immunotherapy was extended to keratinocyte carcinoma (KC), specifically locally advanced and metastasizing basal and squamous cell carcinoma. However, since most KC lesions are non-aggressive, systemic treatment with associated side effects is rarely justified. Conversely, topical immunotherapy with imiquimod remains restricted to premalignant and superficial lesions. Use of laser in the treatment of KC has evolved from physical tumor destruction and laser-assisted drug delivery to laser-mediated immune modulation. Evidence indicates that laser monotherapy can lead to immune cell infiltration, tumor reduction and resistance to tumor re-inoculation. Combining laser with immunotherapeutic agents, termed laser immunotherapy (LIT), may further potentiate immune activation and tumor response. Studies on LIT show not only direct anti-tumor effects but systemic adaptive immunity, illustrated by the prevention of tumor recurrence and regression in distant untreated tumors. These findings imply a therapeutic potential for both local and metastatic disease. This work provides rationales for immune-based treatment of KC and presents the current status of KC immunotherapy. Aiming to expand the field of KC immunotherapy, the review discusses the literature on immune activation following laser monotherapy and LIT.
... Core settings on the ICP-MS were: sample cone depth: 3.9 mm and carrier gas: 0.89 ml/min. The analyzed isotopes were 13 C, 24 Mg, 39 ...
... Two of these were by use of Er:YAG lasers, one in porcine skin in vitro [19], and another into mouse skin [37]. Furthermore, two studies have investigated the combination of AFL and anti-PD-1 antibody treatment of tumors in mice [38,39]. Cao et al. [38] have applied anti-PD-1 antibody topically on AFL-treated tumors, whereas Kawakubo et al. [39] combined local AFL and systemic anti-PD-1 therapy. ...
... Furthermore, two studies have investigated the combination of AFL and anti-PD-1 antibody treatment of tumors in mice [38,39]. Cao et al. [38] have applied anti-PD-1 antibody topically on AFL-treated tumors, whereas Kawakubo et al. [39] combined local AFL and systemic anti-PD-1 therapy. Both studies were resulting in significant tumor reduction or clearance. ...
Background and objectives:
PD-L1 is a tumor ligand that binds to the PD-1 receptor on immune cells, thereby inhibiting the antitumor immune response. The antibody nivolumab is a PD-1 inhibitor, Food and Drug Administration approved for systemic treatment of several aggressive cancer types. Topically applied nivolumab may hold potential as a future strategy to treat keratinocyte cancer, but its molecular properties preclude unassisted topical uptake. The aim of this study was to investigate uptake and biodistribution of topically delivered nivolumab, assisted by two physical enhancement techniques with different delivery kinetics; ablative fractional laser (AFL) and electronically controlled pneumatic injection (EPI).
Study design/materials and methods:
In vitro porcine skin was exposed to CO2 AFL (20 mJ/mb, 5% density), followed by passive diffusion of nivolumab in a Franz cell (1 mg/ml, 18 hours, n = 6) or treated with EPI (4 bar) for immediate delivery of nivolumab (1 mg/ml, 10 minutes, n = 6). The resulting nivolumab skin concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) at three skin depths (100, 500, and 1500 µm), comparing the uptake from assisted delivery with intact skin. Biodistribution of nivolumab in the skin for all interventions was visualized by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and fluorescence microscopy.
Results:
Delivery of nivolumab by AFL-assisted passive diffusion and immediate EPI both resulted in significantly enhanced uptake of nivolumab in all skin depths compared with intact skin (P < 0.05). With AFL, nivolumab concentrations reached 86.3 µg/cm3 (100 µm), 105.8 µg/cm3 (500 µm), and 19.3 µg/cm3 (1500 µm), corresponding to 2-10% of the applied concentration, with the highest deposition in the mid dermis. Immediate EPI delivered 429.4 µg/cm3 (100 µm), 584.9 µg/cm3 (500 µm), and 295.9 µg/cm3 (1500 µm) into the skin, corresponding to 29-58% of the applied nivolumab concentration. From qualitative visualization of the biodistribution, it appeared that nivolumab distributed in a horizontal and continuous homogenous band in the upper and mid dermis through AFL-exposed skin, whereas EPI-delivery showed a deep focal deposition extending into the deep dermis.
Conclusions:
AFL-assisted passive diffusion and immediate EPI-assisted delivery show the potential to deliver therapeutic antibodies locally. Future in vivo and pharmacokinetic studies would reveal the full potential for topical antibody delivery by energy-based devices. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.
... To most accurately represent the flow cytometry data, we performed the flow cytometry after measuring live cell counts within each sample, thereby allowing us to generate data on infiltrating cell densities as accurate as possible (cells/mm 3 ), as has been similarly published [14][15][16][17][18][19][20] . To additionally then analyze the immune phenotype of specific infiltrating immune cell subtypes, we also represented some graphs as percentages of their parent gate. ...
PD‐1 checkpoint inhibitors are used as systemic immunotherapy for locally advanced and metastatic cutaneous squamous cell carcinoma (SCC); however, improved treatment efficacy is urgently needed. In this study, we aimed to investigate the effect of combining systemic anti‐PD‐1 treatment with adjuvant ablative fractional laser (AFL) in a spontaneous SCC mouse model. Tumours induced by ultraviolet radiation in the strain C3.Cg‐ Hr hr /TifBomTac were divided into four groups: anti‐PD‐1‐antibody+AFL ( n = 33), AFL alone ( n = 22) anti‐PD‐1‐antibody alone ( n = 31) and untreated controls ( n = 46). AFL was given at Day 0 (100 mJ/mb, 5% density), while anti‐PD‐1‐antibody (ip, 200 μg) at Days 0, 2, 4, 6 and 8. Response to treatment was evaluated by tumour growth, survival time and by dividing response to treatment into complete responders (clinically cleared tumours), partial responders (reduced tumour growth rate compared to untreated controls) and non‐responders (no decrease in tumour growth rate compared to untreated controls). The strongest tumour response was observed following the combination of systemic anti‐PD‐1 treatment combined with laser exposure, resulting in the highest percentage of complete responders (24%) compared with untreated controls (0%, p < 0.01), AFL monotherapy (13%, p > 0.05) and anti‐PD‐1‐antibody monotherapy (3%, p > 0.05). Moreover, all three treatment interventions demonstrated significantly reduced tumour growth rates compared with untreated controls ( p < 0.01), and the mice had significantly longer survival times ( p < 0.01). In conclusion, the combination treatment revealed an improved treatment effect that significantly enhanced the complete tumour clearance not observed with the monotherapies, indicating a possible additive effect of anti‐PD‐1 with adjuvant AFL in treatment of SCC.
Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.
In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.
In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.
