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

  • Nature. 2024 May;629(8011):417-425. doi: 10.1038/s41586-024-07254-x.
Sebastian B Lacher  #  1 ,  Janina Dörr  #  2 ,  Gustavo P de Almeida  3 ,  Julian Hönninger  1  4 ,  Felix Bayerl  1 ,  Anna Hirschberger  1 ,  Anna-Marie Pedde  1 ,  Philippa Meiser  1 ,  Lukas Ramsauer  1 ,  Thomas J Rudolph  1 ,  Nadine Spranger  1 ,  Matteo Morotti  5  6  7 ,  Alizee J Grimm  5  6  7 ,  Sebastian Jarosch  4  8 ,  Arman Oner  2 ,  Lisa Gregor  2 ,  Stefanie Lesch  2 ,  Stefanos Michaelides  2 ,  Luisa Fertig  2 ,  Daria Briukhovetska  2 ,  Lina Majed  2 ,  Sophia Stock  2  9  10 ,  Dirk H Busch  4 ,  Veit R Buchholz  4 ,  Percy A Knolle  1 ,  Dietmar Zehn  3 ,  Denarda Dangaj Laniti  5  6  7 ,  Sebastian Kobold  2  10  11 ,  Jan P Böttcher  12
Affiliations
  • 1. Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
  • 2. Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.
  • 3. Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, TUM, Freising, Germany.
  • 4. Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, TUM, Munich, Germany.
  • 5. Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.
  • 6. Department of Oncology, University Hospital of Lausanne (CHUV) and UNIL, Lausanne, Switzerland.
  • 7. Agora Cancer Research Center, Lausanne, Switzerland.
  • 8. Boehringer Ingelheim, Biberach, Germany.
  • 9. Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany.
  • 10. German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU University Hospital, Munich, Germany.
  • 11. Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), Neuherberg, Germany.
  • 12. Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 38658748 DOI: 10.1038/s41586-024-07254-x
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.

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