Tumor PDL1-associated DNA damage response inhibitor (DDRi) resistance is STING dependent 3647

Abstract Description Tumor-intrinsic PDL1 promotes the DNA damage response (DDR) and resistance to DDR inhibitors (DDRi). DDR inhibition generates ectopic DNA which activates STING and enhances immunotherapy efficacy. We showed genetic deletion of tumor PDL1 (PDL1KO) sensitizes tumor cells to DDRi, including PARPi and Chk1i, and increases STING activation. Here we show that PDL1-mediated DDRi resistance is dependent on tumor STING. We challenged B16 cells with PDL1KO ± STING knockdown (PDL1KOSTINGlo) into WT mice and treated with PARPi olaparib. Olaparib treated PDL1KO but failed in PDL1KOSTINGlo. Tumor growth significantly decreased in STINGlo tumors regardless of treatment. Together, these data suggest PDL1-dependent STING suppression enhanced tumor control and led to distinct immune outcomes. We have also shown that tumor PDL1-dependent drug sensitization to DDRi is dependent on adaptive immunity. As genetic tumor PDL1KO is not clinically translatable, we identified FDA-approved PDL1-depleting drugs including the cephalosporin antibiotic cefepime. Cefepime-mediated tumor PDL1-depletion phenocopies genetic tumor PDL1KO-mediated DDRi sensitization and STING upregulation and is rapidly clinically translatable. Our data show that tumor PDL1 is an actionable treatment target to improve DDRi efficacy and tumor STING activation. Pharmacologic tumor cell-intrinsic PDL1 depletion with cefepime is a rapidly translatable approach to test. Tumor STING could predict DDRi resistance. Funding Sources Supported by NCI CA252057; NCI CA268641; NCI CA246707; NCI CA292467; TC Gmelich chair; TC Guyre funds. Dartmouth Cancer Center and Dartlab are supported by NCI Cancer Center Support Grant 5P30 CA023108-41. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)