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

Sebastian B. Lacher, Janina Dörr, Gustavo P. 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 and Jan P. Böttcher ()
Additional contact information
Sebastian B. Lacher: Technical University of Munich (TUM)
Janina Dörr: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Gustavo P. Almeida: TUM
Julian Hönninger: Technical University of Munich (TUM)
Felix Bayerl: Technical University of Munich (TUM)
Anna Hirschberger: Technical University of Munich (TUM)
Anna-Marie Pedde: Technical University of Munich (TUM)
Philippa Meiser: Technical University of Munich (TUM)
Lukas Ramsauer: Technical University of Munich (TUM)
Thomas J. Rudolph: Technical University of Munich (TUM)
Nadine Spranger: Technical University of Munich (TUM)
Matteo Morotti: University of Lausanne (UNIL)
Alizee J. Grimm: University of Lausanne (UNIL)
Sebastian Jarosch: TUM
Arman Oner: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Lisa Gregor: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Stefanie Lesch: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Stefanos Michaelides: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Luisa Fertig: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Daria Briukhovetska: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Lina Majed: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Sophia Stock: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Dirk H. Busch: TUM
Veit R. Buchholz: TUM
Percy A. Knolle: Technical University of Munich (TUM)
Dietmar Zehn: TUM
Denarda Dangaj Laniti: University of Lausanne (UNIL)
Sebastian Kobold: LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich
Jan P. Böttcher: Technical University of Munich (TUM)

Nature, 2024, vol. 629, issue 8011, 417-425

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07254-x

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