PuSH - Publikationsserver des Helmholtz Zentrums München: PGE<sub>2</sub> limits effector expansion of tumour-infiltrating stem-like CD8<sup>+</sup> T cells.

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Lacher, S.B.* ; Dörr, J.* ; de Almeida, G.P.* ; Hönninger, J.* ; Bayerl, F.* ; Hirschberger, A.* ; Pedde, A.M.* ; Meiser, P.* ; Ramsauer, L.* ; Rudolph, T.J.* ; Spranger, N.* ; Morotti, M.* ; Grimm, A.J.* ; Jarosch, S.* ; Oner, A.* ; Gregor, L.* ; Lesch, S.* ; Michaelides, S.* ; Fertig, L.* ; Briukhovetska, D.* ; Majed, L.* ; Stock, S.* ; Kobold, S. ; Böttcher, J.P.*

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

Nature 629, 417-425 (2024)

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Cancer-specific TCF1⁺ stem-like CD8⁺ T cells can drive protective anticancer immunity through expansion and effector cell differentiation^1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies^2,5-9 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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PuSH - Publikationsserver des Helmholtz Zentrums München

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

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