PAD4 controls the anti-tumor response by fine-tuning IFNγ signaling in macrophages

Abstract MHC-II–mediated antigen presentation is essential for the function of immune system. Recent evidence indicates that MHC-II expression shapes tumor immunity and response to immunotherapy. expressing presenting cells (APCs) mediate CD4 +T-cell priming activation license them support CD8 response. Citrullination – catalyzed by peptidyl arginine deiminases (PADs) a post-translational modification at residues. Here, we show PAD4 negatively regulates anti-tumor tuning IFNγ-signaling gene expression, including MHC-II, in associated macrophages (TAMs) bearing mouse models. Mechanistically, citrullinates STAT1, thereby promoting interaction between STAT1 PIAS1 (protein inhibitor activated STAT1) resulting reduced TAMs. Moreover, low levels TAMs correlate with immunotherapy are poor cancer patient survival. These data suggest targeting PAD4-mediated citrullination may serve as potential anti-cancer therapeutic approach. Supported grants from NCI (R01CA217510, PA-21-071)