Abstract 1398: Caspase-1 dependent lytic cell death influences intra-tumoral neutrophil-to-lymphocyte ratio that limits chemotherapy efficacy

Abstract Chemotherapy remains a cornerstone in the treatment of bladder cancer, with most studies emphasizing its direct cytotoxic effects to induce tumor cell death. However, the influence of various cell death modalities—such as apoptosis, pyroptosis, necroptosis, and ferroptosis—on the immune system remains underexplored. These modalities can either promote an immunogenic response or foster immunosuppression, notably through mechanisms such as altering the neutrophil-to-lymphocyte ratio (NLR), which can impact chemotherapy efficacy. In our study, we observed that gemcitabine treatment in a murine bladder cancer model enriched for a caspase-1-dependent lytic cell death that was non-immunogenic and contributed to an immunosuppressive tumor microenvironment by increasing intra-tumoral NLR. Notably, genetic deletion of caspase-1 shifted this non-immunogenic cell death to an immunogenic form. Additionally, pharmacological inhibition of caspase-1 using VX-765 provided therapeutic benefits by reducing NLR, significantly suppressing tumor growth. While lytic or pyroptotic cell death may be advantageous in the context of infections, our findings highlight a paradox: in the context of chemotherapy treatment, caspase-1-dependent lytic cell death/ pyroptosis can play a detrimental role by promoting an immunosuppressive environment that limits efficacy. These results underscore the importance of understanding and modulating cell death pathways to optimize therapeutic outcomes in cancer. Citation Format: Stephen (Qi Rong) Wong, Ethan Subel, Kazukuni Hayashi, Hongbo Gao, Fotis Nikolo, Keith Chan. Caspase-1 dependent lytic cell death influences intra-tumoral neutrophil-to-lymphocyte ratio that limits chemotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1398.