1278 Blocking tumor-intrinsic caspase-1 inflammasome sensitizes melanoma response to anti-PD1 therapy by rejuvenating dysfunctional CD8 T cells

Anti-PD1 therapy revolutionized melanoma treatment, yet low response rates and immune-related adverse events remain a major concern. Caspase-1 inflammasome is autonomously active in known to promote tumor progression. Therefore, we investigated its role immunotherapy resistance melanoma. The pharmacological inhibition of caspase-1 augmented mouse (B16F10 YUMM1.7) anti-PD1 vivo. combination studies using knockout (KO) cells KO mice revealed that tumor-intrinsic but not tumor-extrinsic hampered the induced dysfunctional CD8 T microenvironment (TME). Similarly, an anti-PD1-resistant human cell line (1205Lu) sensitized immune system model (BALB/c;Rag2-/-;IL-2Rγc-/-;SIRPαNOD) reconstituted with (CD34+ cord blood cells). To understand mechanisms leading T-cell dysfunction, studied 2 transcription factors, TCF1 (stemness) TOX (dysfunctional phenotype), critical for function, differentiation, fate. Control anti-PD1-treated tumors showed high TCF1, which was reversed by anti-caspase-1 treatment In vitro melanoma-conditioned media (MCM) NFAT/IRF4/BTAF signaling TOX, PD1, TIM3, suppressed decreased proliferation, controlled MCM from cells. Together, demonstrate benefits rejuvenating functionality.