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

Abstract

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