2. Academic Validation
  3. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells

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

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. j.boettcher@tum.de.
  • # 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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