The nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes are involved in several physiological functions. However, their roles in keratinocyte responses to UV radiation have not been clearly elucidated. This study shows that, among other NOX family members, UVB irradiation results in a biphasic activation of NOX1 that plays a critical role in defining keratinocyte fate through the modulation of the DNA damage response network. Indeed, suppression of both bursts of UVB-induced NOX1 activation by using a specific peptide inhibitor of NOX1 (InhNOX1) is associated with increased nucleotide excision repair efficiency and reduction of apoptosis, which is finally translated into decreased photocarcinogenesis. On the contrary, when only the second peak of UVB-induced NOX1 activation is blocked, both nucleotide excision repair efficiency and apoptosis are decreased. Our results show that inhibition of NOX1 activation could be a promising target for the prevention and treatment of UVB-induced skin cancer in nucleotide excision repair-proficient and -deficient patients.
Sarcomas are heterogeneous malignant mesenchymal neoplasms with limited sensitivity to immunotherapy. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of sarcoma patients treated with pembrolizumab. While the KP has already been described to favor immune escape through the degradation of L-Tryptophan and production of metabolites including L-Kynurenine, Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP, still represents an attractive therapeutic target, and its blockade had not yet been investigated in sarcomas. Using immunohistochemistry, IDO1 and CD8, expression profiles were addressed within 203 cases of human sarcomas. At a preclinical level, we investigated the modulation of the KP upon PDL1 blockade in a syngeneic model of sarcoma through mRNA quantification of key KP enzymes within the tumor. Furthermore, in order to evaluate the possible anti-tumor effect of IDO blockade in combination with PDL1 blockade, an innovative IDO inhibitor (GDC-0919) was used. Its effect was first assessed on Kynurenine to Tryptophan ratio at plasmatic level and also within the tumor. Following GDC-0919 treatment, alone or in combination with anti-PDL1 antibody, tumor growth, immune cell infiltration, and gene expression profiling were measured. IDO1 expression was observed in 39.1% of human sarcoma cases and was significantly higher in tumors with high CD8 infiltration. In the pre-clinical setting, blockade of PDL1 led to a strong anti-tumor effect and was associated with an intratumoral inflammatory cytokines signature driven by Ifng but also with a modulation of the KP enzymes including Ido1 and Ido2. IDO1 inhibition using GDC-0919 resulted in (i) a significant decrease of plasmatic Kynurenine to Tryptophan ratio and in (ii) a decrease of tumoral Kynurenine. However, GDC-0919 used alone or combined with anti-PDL1, did not show anti-tumoral activity and did not affect the tumor immune cell infiltrate. In order to elucidate the mechanism(s) underlying the lack of effect of GDC-0919, we analyzed the gene expression profile of intratumoral biopsies. Interestingly, we have found that GDC-0919 induced a downregulation of the expression of pvr and granzymes, and an upregulation of inhba and Dtx4 suggesting a potential role of the IDO pathway in the control of NK function.
The leading cause of cutaneous squamous cell carcinomas (cSCCs) is exposure to ultraviolet radiation (UV). Unlike most other cancers, the incidence rates of cSCCs are still on the rise and the treatment options currently available are limited. We have recently found that dihydroorotate dehydrogenase (DHODH), which is the rate-limiting enzyme in the de novo pyrimidine synthesis pathway, plays a critical role in UVB-induced energy metabolism reprogramming. Using a multistage model of UVB radiation-induced skin cancer, we show that UVB-induced DHODH upregulation is mainly regulated transcriptionally by STAT3. Our results indicate that chronic inhibition of DHODH by leflunomide (LFN) blocks UVB-induced tumor initiation. Human tumor xenograft studies showed that LFN treatment reduces growth of established tumors when used in combination with a genotoxic agent, 5-fluorouracil (5-FU). Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.
Background: While antiangiogenic therapies have been shown effective in preclinical and clinical trials, tumors can acquire resistance conferring them the ability to survive and grow under hypoxic conditions, even, induced by antiangiogenic drugs themselves. Methods: This study investigated the effects of an antiangiogenic strategy and hypoxia-regulating agent, each alone and in combination. Here, we have tested the synergistic activity of the anti-angiogenic agent Sunitinib and the mTOR inhibitor Everolimus in murine syngeneic renal cancer model - renal carcinoma being known as angiogenesis-dependent and hypoxia-driven malignancy. Anti-tumor effects were investigated on tumor growth and survival. Flow cytometry-based immunoprofiling was performed at the peripheral level - blood and spleen - while immunohistofluorescence and quantitative image analysis served to characterize and evaluate tumor immune cell infiltrate, tumor hypoxia, and tumor vascular density/features. Results: While Sunitinib and more importantly Everolimus led to a significant tumor growth inhibition as single agents, their combination was more effective on tumor regression. At the peripheral level, Sunitinib, but also Everolimus, led each to declines in circulating and splenic myeloid-derived suppressor cells (MDSCs) - depicted as CD11b+/Gr1+, an event that was further optimized upon combination of both agents. In addition, tumor sections analyses showed decreased microvessel density under Sunitinib and combination treatment. Differential modulations of correlative endothelium/pericytes staining and hypoxia degree were also observed upon the different treatments. This study confirms the preclinical efficacy of Sunitinib and a hypoxia regulator in renal tumor model and suggests that limitation of Sunitinib-induced hypoxia through mTOR targeting or with hypoxia regulators represents a suitable strategy to enhance effect of anti-angiogenic agent thereby limiting tumor growth. Citation Format: Imane Nafia, Assia Chaibi, Doriane Bortolotto, Christophe Rey, Alban Bessede. Anti-angiogenic therapy combination with hypoxia-regulating agent leads to improved tumor regression in a murine model or renal carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3938.
Background: Soft Tissue Sarcoma (STS) is known to be resistant to cancer immunotherapy including the prototypical immune checkpoint inhibitor (ICI) anti-PD1 (1). It’s therefore crucial to develop innovative strategies aiming at improving current clinical benefit. To this end, a well-characterized sarcoma preclinical model that mimics resistance to immunotherapy is needed. Starting from the anti-PD(L)1-sensitive MCA205 sarcoma mouse model, we therefore aimed at developing and characterizing a novel model resistant to anti-PD1. Methods: Anti-PDL1 antibody was first administered to the ICI-sensitive MCA205 mouse sarcoma model (MCA205-S) and tumor growth was followed overtime. Tumor from a “non-responder” animal - tumor growth profile being similar as in the vehicle group - was then retrieved and processed for tissue dissociation and cell culture. Tumor cells were then amplified and inoculated into immunocompetent C57BL/6 mice that were exposed or not to anti-PD1 antibody, and tumor growth was monitored for a 8-week period. In addition, tumor samples from satellite animals were collected and processed for intratumoral immune landscape characterization by multiparametric flow cytometry as well as for gene expression analysis by RNA sequencing. Results: While anti-PD1 antibody demonstrated a strong anti-tumor effect in MCA205-S tumor-bearing mice, administration of anti-PD1 to the mice inoculated with the non-responder mouse-originating MCA205 cells did not yield to a significant anti-tumor effect thereby validating the resistant profile of this new MCA205-R cell line. Flow cytometry analysis of tumor-infiltrated immune cells revealed a higher abundance of macrophages (defined as CD11b+/F4:80+) in MCA205-R when compared to the MCA205-S model, which more likely harbor a M2 phenotype. Also, anti-PD1 treatment favored an important MCA205-R tumor infiltration by gMDSC which was more limited in the MCA205-S model. Gene expression profile of tumor samples is currently under investigation. Conclusions: We developed and validated a novel preclinical mouse model of sarcoma (MCA205-R) characterized by its resistance to anti-PD1 and a high tumor infiltration by macrophages. This model - more reflecting the clinic in terms of immunotherapy sensitivity - can thus serve to evaluate novel immunotherapeutic regimens either alone or in combination with reference ICI, to ultimately translate into clinical benefit for STS patients treated with immunotherapy. Citation Format: Imane Nafia, Jean-Philippe Guegan, Assia Chaibi, Noëlie Bos, Doriane Bortolotto, Christophe Rey, Loïc Cerf, Florent Peyraud, Antoine Italiano, Alban Bessede. Development and characterization of a novel anti-PD1 resistant sarcoma mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 622.
Background: In the context of novel immuno-oncology therapeutics development at preclinical stage, it's crucial to understand the primary features of the in-vivo model to be used and to delineate mechanisms underlying response to a drug candidate. While PDL1 blockade figures as a gold standard immunotherapy its exact mechanism of action in a mouse model of sarcoma remains to be elucidated. Methods: Using a preclinical syngeneic mouse model of sarcoma based on the inoculation of MCA205 cell line we investigated anti-tumor effect of anti-PDL1 antibody through tumor growth and survival assessment. Using the same experimental setting, and by mean of intratumoral microdialysis, immune-related metabolic pathways at both tumor and contralateral sites were assessed. Tumor samples were also collected for gene expression analysis by RNA sequencing. Also, immune landscape of the tumor was addressed by both flow cytometry analysis and by multiparametric immunohistofluorescence and image analysis. Finally, participation of CD8 T cells was investigated using a specific depleting antibody-based strategy. Results: As expected, administration of anti-PDL1 antibody led to a strong anti-tumor response. With respect to the immunometabolism features of this model, it displays within the tumor - and compared to the non-tumor bearing area - i) a slight Kynurenine pathway activation, ii) a strong Arginase activity, and iii) a high Adenosine production. Interestingly, anti-PDL1 effect was associated with a limitation of Adenosine level within the tumor thus arguing for an important role of the Adenosine axis in the control of the anti-tumor immune response. Along with this effect, PDL1 blockade led to an intratumoral enrichment of leukocytes (CD45+), with a higher abundance of lymphocytes also displaying increased level of IFNgamma. In contrast, macrophages - delineated as CD11b+/F4:80+ - were limited upon treatment, especially the immunosuppressive CD11b/Gr1Low/Int cell subsets while concomitantly promoting a M1/M2 macrophages ratio. Along with these data, RNAseq analysis revealed an enrichment in genes from immune-related datasets including interferon signaling. Interestingly, CD8 depletion fully abrogated anti-PDL1 anti-tumor effect thus confirming the critical role of this population. Conclusions: Altogether, this new multiparametric dataset collected on a preclinical model of sarcoma allows the highlighting of specific intrinsic features of the model, and certainly provides a deeper understanding of the mechanism of action of an effective and approved drug. Such a comprehensive assessment-based strategy can therefore serve as a basis for further exploration of novel candidates. Citation Format: Imane Nafia, Assia Chaibi, Doriane Bortolotto, Christophe Rey, Antoine Italiano, Alban Bessede. Deciphering anti-PDL1 effect in a syngeneic mouse model of sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6658.
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