Title: Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP
Author: Yi Zhou, Mingjian Fei, Gu Zhang, Wei-Ching Liang, WeiYu Lin, Yan Wu, Robert Piskol, John Ridgway, Erin McNamara, Haochu Huang, Juan Zhang, Jaehak Oh, Jaina M. Patel, Diana Jakubiak, Jeff Lau, Beth Blackwood, Daniel D. Bravo, Yongchang Shi, Jianyong Wang, Hong-Ming Hu, Wyne P. Lee, Rajiv Jesudason, Dewakar Sangaraju, Zora Modrusan, Keith R. Anderson, Sren Warming, Merone Roose-Girma, Minhong Yan
Issue&Volume: February 11, 2020
Abstract: Clearance of apoptotic cells by macrophages prevents excessive inflammation and supportsimmune tolerance. Here, we examined the effect of blocking apoptotic cell clearanceon anti-tumor immune response. We generated an antibody that selectively inhibitedefferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulationof apoptotic cells within tumors and triggered a type I interferon response. Treatmentof tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergizedwith anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTKtreatment was lost in Stinggt/gt mice, but not in Cgas/ mice. Abolishing cGAMP production in Cgas/ tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7Rchannel also compromised the effects of MerTK blockade. Mechanistically, extracellularATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophagesand subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicityand potentiates anti-tumor immunity, which has implications for cancer immunotherapy.