{Reference Type}: Journal Article
{Title}: PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
{Author}: Lacher SB;Dörr J;de Almeida GP;Hönninger J;Bayerl F;Hirschberger A;Pedde AM;Meiser P;Ramsauer L;Rudolph TJ;Spranger N;Morotti M;Grimm AJ;Jarosch S;Oner A;Gregor L;Lesch S;Michaelides S;Fertig L;Briukhovetska D;Majed L;Stock S;Busch DH;Buchholz VR;Knolle PA;Zehn D;Dangaj Laniti D;Kobold S;Böttcher JP;
{Journal}: Nature
{Volume}: 629
{Issue}: 8011
{Year}: 2024 May 24
{Factor}: 69.504
{DOI}: 10.1038/s41586-024-07254-x
{Abstract}: 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.