PAD4 controls tumor immunity via restraining MHC-II machinery in macrophages

Submission 8

Tuesday-Talks 3-Selected talk-03

Presented by: Michael Pitter

Michael Pitter ^{1, 2, 3}, Hongjuan Zhang ^{1, 2}, Nisha Nagarsheth ^{1, 2}, Houjun Xia ^{1, 2}, Ilona Kryczek ^{1, 2}, Weiping Zou ^{1, 2, 3}

¹ Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
² Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
³ Department of Pathology, University of Michigan, Ann Arbor, MI, 48109

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 IFNg-signaling gene expression, including 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. The data suggest that targeting PAD4-mediated citrullination may serve as a potential anti-cancer therapeutic approach.