PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
Details
Serval ID
serval:BIB_32E213209E57
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
Journal
Nature
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
In Press
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Publication Status: aheadofprint
Abstract
Cancer-specific TCF1 <sup>+</sup> stem-like CD8 <sup>+</sup> T cells can drive protective anticancer immunity through expansion and effector cell differentiation <sup>1-4</sup> ; however, this response is dysfunctional in tumours. Current cancer immunotherapies <sup>2,5-9</sup> can promote anticancer responses through TCF1 <sup>+</sup> stem-like CD8 <sup>+</sup> T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1 <sup>+</sup> CD8 <sup>+</sup> T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE <sub>2</sub> ) restricts the proliferative expansion and effector differentiation of TCF1 <sup>+</sup> CD8 <sup>+</sup> T cells within tumours, which promotes cancer immune escape. PGE <sub>2</sub> does not affect the priming of TCF1 <sup>+</sup> CD8 <sup>+</sup> T cells in draining lymph nodes. PGE <sub>2</sub> acts through EP <sub>2</sub> and EP <sub>4</sub> (EP <sub>2</sub> /EP <sub>4</sub> ) receptor signalling in CD8 <sup>+</sup> T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 <sup>+</sup> tumour-infiltrating CD8 <sup>+</sup> T lymphocytes (TILs). Ablation of EP <sub>2</sub> /EP <sub>4</sub> signalling in cancer-specific CD8 <sup>+</sup> 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 <sub>2</sub> -mediated inhibition of TCF1 <sup>+</sup> TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 <sup>+</sup> TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE <sub>2</sub> -EP <sub>2</sub> /EP <sub>4</sub> axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
Pubmed
Open Access
Yes
Create date
29/04/2024 10:37
Last modification date
30/04/2024 7:06