No abstract

Highlights d NK cells drive broad inflammatory remodeling characteristic of T-cell-inflamed tumors d PGE2 acting on EP2 and EP4 on NK cells prevents the TME switch enabling immune escape d Opposing inflammatory profiles found in many human cancer types have prognostic value d A signature capturing pro-and anti-tumor factors predicts response to immunotherapy

Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE 2 /EP2-4 pathway with widely used non-steroidal and steroidal antiinflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from non-responders shortly following treatment and identified acute IFN-γ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX-2 inhibitors or EP2-4 PGE 2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE 2 /EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot.