1. PGE 2 limits effector expansion of tumour-infiltrating stem-like CD8 + T cells.
- Author
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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, and Böttcher JP
- Subjects
- Animals, Female, Humans, Male, Mice, Cell Differentiation, Cell Line, Tumor, Disease Models, Animal, Hepatocyte Nuclear Factor 1-alpha metabolism, Interleukin-2, Lymph Nodes cytology, Lymph Nodes immunology, Mice, Inbred C57BL, Receptors, Prostaglandin E, EP2 Subtype deficiency, Receptors, Prostaglandin E, EP2 Subtype metabolism, Receptors, Prostaglandin E, EP4 Subtype deficiency, Receptors, Prostaglandin E, EP4 Subtype metabolism, Signal Transduction, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Proliferation, Dinoprostone metabolism, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Neoplasms immunology, Neoplasms prevention & control, Stem Cells cytology, Stem Cells immunology, Stem Cells metabolism, Tumor Escape immunology
- 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., (© 2024. The Author(s).)- Published
- 2024
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