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

• 成果类型: Article
• 署名作者: Lacher, Sebastian B.; Doerr, Janina; de Almeida, Gustavo P.; Hoenninger, 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; Majed, Lina; Stock, Sophia; Busch, Dirk H.; Buchholz, Veit R.; Knolle, Percy A.; Zehn, Dietmar; Dangaj Laniti, Denarda; Kobold, Sebastian; Boettcher, Jan P.
• 署名单位: Technical University of Munich; University of Munich; University of Munich; Technical University of Munich; Technical University of Munich; University of Lausanne; Ludwig Institute for Cancer Research; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Munich; Helmholtz Association; German Cancer Research Center (DKFZ); University of Munich; Boehringer Ingelheim
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4053
• DOI: 10.1038/s41586-024-07254-x
• 发表日期: 2024-05-02
• 页码: 43-44
• 关键词: trafficking; cdc1; prostaglandin-e2; responses; survival; immunity; subset

摘要

Cancer-specific TCF1(+) stem-like CD8(+) T cells can drive protective anticancer immunity through expansion and effector cell differentiation(1,2,3,4); however, this response is dysfunctional in tumours. Current cancer immunotherapies(2,5,6,7,8,9) 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 (PGE(2)) restricts the proliferative expansion and effector differentiation of TCF1(+)CD8(+) T cells within tumours, which promotes cancer immune escape. PGE(2) does not affect the priming of TCF1(+)CD8(+) T cells in draining lymph nodes. PGE(2) 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 PGE(2)-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 PGE(2)-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.