PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.

Autor: Lacher, Sebastian B., Dörr, Janina, de Almeida, Gustavo P., Hönninger, Julian, Bayerl, Felix, Hirschberger, Anna, Pedde, Anna-Marie, Meiser, Philippa, Ramsauer, Lukas, Rudolph, Thomas J., Spranger, Nadine, Morotti, Matteo, Grimm, Alizee J., Jarosch, Sebastian, Oner, Arman, Gregor, Lisa, Lesch, Stefanie, Michaelides, Stefanos, Fertig, Luisa, Briukhovetska, Daria
Zdroj: Nature; May2024, Vol. 629 Issue 8011, p417-425, 9p
Abstrakt: 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.Tumour-derived prostaglandin E2, signaling through its receptors EP2 and EP4, is shown to restrain the responses of tumour-infiltrating stem-like TCF1+CD8+ T lymphocytes, and modulation of T cell EP2 and EP4 can restore anticancer immunity. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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