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Tumor-intrinsic P2RY6 drives immunosuppression by enhancing PGE2 production
Xilong Xu1, Yi Lu2, Longzhi Cao3
1College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China.
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.
Insights
Aberrant P2RY6 expression in tumors drives immune evasion and immunotherapy resistance. Targeting this pyrimidinergic receptor could overcome treatment unresponsiveness in cancer patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Anti-programmed cell death-1 (anti-PD-1) immunotherapy shows promise but faces challenges with patient unresponsiveness and lack of predictive biomarkers.
- Identifying novel targets is crucial for improving cancer treatment efficacy.
Purpose of the Study:
- To investigate the role of the pyrimidinergic receptor P2RY6 in cancer immune evasion and immunotherapy resistance.
- To explore P2RY6 as a potential therapeutic target for enhancing anti-PD-1 efficacy.
Main Methods:
- Analysis of P2RY6 expression in human cancers.
- Utilized mouse syngeneic and human xenograft tumor models to assess P2RY6 function.
- Investigated downstream signaling pathways, including Gq/phospholipase C-β and prostaglandin E2 synthesis.
Main Results:
- Aberrant P2RY6 expression is frequent in human cancers and promotes immune evasion.
- Ectopic P2RY6 expression enhances tumor growth and immunotherapy resistance by creating an immunosuppressive tumor microenvironment (TME).
- P2RY6 deletion in tumors with high expression reverses immunosuppression, inhibiting tumor growth via prostaglandin E2 signaling.
Conclusions:
- P2RY6 is a key driver of tumor-induced immunosuppression and resistance to anti-PD-1 therapy.
- Targeting tumor-intrinsic P2RY6 represents a promising strategy for precision immunotherapy in specific cancer patient populations.
- Global P2ry6 deletion in mice does not affect viability, suggesting a favorable safety profile for targeting P2RY6 in tumors.
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