Tumor-intrinsic P2RY6 drives immunosuppression by enhancing PGE2 production

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. [Display omitted] •Aberrant P2RY6 expression is common in human cancers•Tumor-intrinsic P2RY6 promotes immune evasion•P2RY6 enhances cyclooxygenase expression to promote PGE2 production Despite the efficacy of anti-PD-1 immunotherapy, many patients remain unresponsive, and predictive biomarkers are needed. Xu et al. identify P2RY6 as a key driver of immune evasion in cancers, promoting an immunosuppressive tumor microenvironment and resistance to immunotherapy, thus nominating P2RY6 as a precision immunotherapy target.