%0 Journal Article
%T PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
%A Lacher SB
%A Dörr J
%A de Almeida GP
%A Hönninger J
%A Bayerl F
%A Hirschberger A
%A Pedde AM
%A Meiser P
%A Ramsauer L
%A Rudolph TJ
%A Spranger N
%A Morotti M
%A Grimm AJ
%A Jarosch S
%A Oner A
%A Gregor L
%A Lesch S
%A Michaelides S
%A Fertig L
%A Briukhovetska D
%A Majed L
%A Stock S
%A Busch DH
%A Buchholz VR
%A Knolle PA
%A Zehn D
%A Dangaj Laniti D
%A Kobold S
%A Böttcher JP
%J Nature
%V 629
%N 8011
%D 2024 May 24
%M 38658748
%F 69.504
%R 10.1038/s41586-024-07254-x
%X Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 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 TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) 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 EP2/EP4 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 PGE2-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 PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.