Tumor-intrinsic P2RY6 drives immunosuppression by enhancing PGE2 production
Xilong Xu,
Yi Lu,
Longzhi Cao,
Yang Miao,
Yamei Li,
Yue Cui,
Ting Han
Affiliations
Xilong Xu
College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China
Yi Lu
National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
Longzhi Cao
National Institute of Biological Sciences, Beijing 102206, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Yang Miao
National Institute of Biological Sciences, Beijing 102206, China; PTN Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
Yamei Li
National Institute of Biological Sciences, Beijing 102206, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Yue Cui
College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China
Ting Han
College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China; Corresponding author
Summary: Despite the success of anti-programmed cell death-1 (anti-PD-1) immunotherapy, many cancer patients remain unresponsive, and reliable predictive biomarkers are lacking. Here, we show that aberrant expression of the pyrimidinergic receptor P2RY6 is frequent in human cancers and causes immune evasion. In mouse syngeneic and human xenograft tumor models, ectopic expression of P2RY6 shapes an immunosuppressive tumor microenvironment (TME) to enhance tumor growth and resistance to immunotherapy, whereas deletion of P2RY6 from tumors with high P2RY6 expression inflames the TME to inhibit tumor growth. As a G protein-coupled receptor, P2RY6 activates Gq/phospholipase C-β signaling and stimulates the synthesis of prostaglandin E2, which is a key mediator of immunosuppression in the TME. In contrast to the essential role of P2RY6 in tumors, global deletion of P2ry6 from mice does not compromise viability. Our study thus nominates P2RY6 as a precision immunotherapy target for patients with high tumor-intrinsic P2RY6 expression.
