Abstract 994: Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects

Abstract

Abstract Introduction: Melanoma NLRP3 inflammasome activation is involved in tumor progression and melanoma-induced immunosuppression via IL-1β-mediated effect. Abstract: Melanoma-associated inflammation participates in the generation of a tumor permissive environment, which promotes tumor progression and metastasis. The pro-inflammatory cytokine IL-1β mediates several inflammatory diseases and the modulation of the immune system. In the context of malignancy, IL-1β is a validated target in mouse models of cancer, including melanoma, where the cytokine contributes to immunosuppression, angiogenesis, metastasis, and regulation of myeloid derived suppressor cells. In this study, we demonstrate that the NLRP3 inflammasome drives the maturation of the pro-inflammatory cytokine IL-1β in melanoma cells. Accordingly, analysis of melanoma biopsies (N=461) showed increased NLRP3 expression in the lesions which correlates with the IL-1β levels. In melanoma-bearing mice, NLRP3 inhibition with a clinically evaluated NLRP3 inflammasome inhibitor OLT1177 (dapansutrile), showed to decrease melanoma progression and tumor-induced inflammation reducing the circulating levels of IL-6, G-CSF, and VEGF compared to vehicle tumor-bearing mice. Analysis of myeloid-derived suppressor cell (MDSC) populations revealed that NLRP3 inflammasome inhibition was sufficient to prevent MDSCs expansion (both PMN-MDSCs and M-MDSCs), restoring the population to the non-tumor-bearing level. The effect observed on MDSCs in tumor-bearing mice following NLRP3 inhibition resulted in increased NK cells activation in primary tumors (Figure). These data establish a new correlation between IL-1β, NLRP3, melanoma-induced immunosuppression and tumor progression. Considering that NLRP3 inhibition resulted in decreased tumor-induced immune evasion as well as an increased tumoricidal immune response, we evaluated the effect of the addition of NLRP3 inhibition to checkpoint inhibition. Tumor bearing mice treated with OLT1177 and anti-PD-1 showed reduced tumor progression compared to the single-agent treatments. In conclusion, NLRP3 inflammasome inhibition was successful in preventing IL-1β processing in melanoma cells and tumor progression. These findings suggest that NLRP3 may represent a potential therapeutic target for melanoma. Citation Format: Carlo Marchetti, Isak Tengesdal, Charles Dinarello, Mayumi Fujita. Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects [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 994.