AI Article Synopsis
- Anti-PD-1 immunotherapy shows promise, but many cancer patients do not respond, highlighting the need for better predictive biomarkers.
- The study reveals that the receptor P2RY6 is often overexpressed in cancers, promoting immune evasion and creating a tumor microenvironment that supports tumor growth and resistance to immunotherapy.
- Targeting P2RY6 could offer a precision immunotherapy strategy for patients with tumors exhibiting high levels of this receptor, as its absence does not adversely affect overall mouse health.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.celrep.2024.114469 | DOI Listing |
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