Mechanisms of cell death in cutaneous melanoma

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PROJECT SUMMARY The incidence of cutaneous melanoma is rising. While small molecule targeted inhibitors and immune checkpoint antibodies have increased long-term survival in advanced-stage cutaneous melanoma, many patients still do not benefit and regimens are associated with high toxicity. We are studying the determinants of treatment response and mechanisms of resistance in melanoma. From our studies, we aim to generate pre- clinical data for new combinations that delay/prevent the onset of acquired resistance while minimizing patient toxicities in order to improve patient survival and quality of life. Multiple clinical trials have emanated from our work (NCT03580382, NCT02012231, NCT02683395). Tumor immunogenicity, defined as the ability of the tumor itself to trigger an anti-tumor adaptive immune response, is one of the most important determinants of successful anti-cancer therapy. The immunogenicity of a tumor depends on its antigenicity, conferred by neo- antigens, and also by adjuvant effects triggered by damage-associated molecular patterns (DAMPs) released from stressed or dying tumor cells during a process called immunogenic cell death (ICD). We recently discovered a signaling pathway that allows efficient release of DAMPs from dying cells by switching apoptosis into a potentially immunogenic form of cell death called pyroptosis. Mechanistically, activation of caspase-3 during apoptosis leads to cleavage of gasdermin E (GSDME), generating a pore-forming GSDME-N fragment. GSDME-N pores allow release of intracellular DAMPs such as HMGB1, DNA, and ATP. The ability of this novel pathway to switch apoptosis into pyroptosis suggests that GSDME-induced pyroptosis is likely a key effector of cancer cell immunogenicity and may determine their successful response to various anti-cancer therapies. Supporting this hypothesis, our preliminary data revealed that efficient BRAFi + MEKi-induced anti- tumor immune responses in melanoma cells are dependent, at least in part, on the pyroptotic activity of GSDME. The goals of this application are to define mechanisms underlying BRAFi + MEKi regulation of GSDME and pyroptosis in melanoma and to investigate how GSDME-induced pyroptosis alters the effects of immune checkpoint inhibitors. The standard of care for melanomas is immune checkpoint inhibition, specifically anti-PD-1 (pembrolizumab and nivolumab) and anti-CTLA-4 (ipilimumab). Immune checkpoint inhibitors are efficacious in some melanoma patients; however, many do not respond. Other patients who initially respond, ultimately progress. This proposal is designed to utilize targeted therapies to optimize up-front immune checkpoint inhibitors as well as invigorating the immune system in resistant tumors. Thus, we aim to develop new therapeutic strategies that will address clinical unmet needs in the melanoma field.