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

Sebastian B Lacher,Janina Dörr, Gustavo P de Almeida, Julian Hönninger,Felix Bayerl,Anna Hirschberger, Anna-Marie Pedde, Philippa Meiser, Lukas Ramsauer, Thomas J Rudolph, Nadine Spranger, Matteo Morotti,Alizee J Grimm,Sebastian Jarosch,Arman Oner, Lisa Gregor,Stefanie Lesch,Stefanos Michaelides, Luisa Fertig,Daria Briukhovetska,Lina Majed,Sophia Stock, Dirk H Busch, Veit R Buchholz,Percy A Knolle, Dietmar Zehn,Denarda Dangaj Laniti,Sebastian Kobold,Jan P Böttcher

Nature(2024)

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摘要
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.
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