PGE limits effector expansion of tumour-infiltrating stem-like CD8 T cells.

Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1CD8 T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE) restricts the proliferative expansion and effector differentiation of TCF1CD8 T cells within tumours, which promotes cancer immune escape. PGE does not affect the priming of TCF1CD8 T cells in draining lymph nodes. PGE acts through EP and EP (EP/EP) receptor signalling in CD8 T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 tumour-infiltrating CD8 T lymphocytes (TILs). Ablation of EP/EP signalling in cancer-specific CD8 T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE-mediated inhibition of TCF1 TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE-EP/EP axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.