PGE 2 limits effector expansion of tumour-infiltrating stem-like CD8 + T cells.

Autor: Lacher SB; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Dörr J; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., de Almeida GP; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, TUM, Freising, Germany., Hönninger J; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, TUM, Munich, Germany., Bayerl F; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Hirschberger A; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Pedde AM; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Meiser P; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Ramsauer L; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Rudolph TJ; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Spranger N; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Morotti M; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.; Department of Oncology, University Hospital of Lausanne (CHUV) and UNIL, Lausanne, Switzerland.; Agora Cancer Research Center, Lausanne, Switzerland., Grimm AJ; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.; Department of Oncology, University Hospital of Lausanne (CHUV) and UNIL, Lausanne, Switzerland.; Agora Cancer Research Center, Lausanne, Switzerland., Jarosch S; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, TUM, Munich, Germany.; Boehringer Ingelheim, Biberach, Germany., Oner A; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Gregor L; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Lesch S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Michaelides S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Fertig L; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Briukhovetska D; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Majed L; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany., Stock S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.; Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU University Hospital, Munich, Germany., Busch DH; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, TUM, Munich, Germany., Buchholz VR; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, TUM, Munich, Germany., Knolle PA; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany., Zehn D; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, TUM, Freising, Germany., Dangaj Laniti D; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.; Department of Oncology, University Hospital of Lausanne (CHUV) and UNIL, Lausanne, Switzerland.; Agora Cancer Research Center, Lausanne, Switzerland., Kobold S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU University Hospital, Munich, Germany.; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), Neuherberg, Germany., Böttcher JP; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany. j.boettcher@tum.de.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 May; Vol. 629 (8011), pp. 417-425. Date of Electronic Publication: 2024 Apr 24.
DOI: 10.1038/s41586-024-07254-x
Abstrakt: 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 (PGE 2 ) restricts the proliferative expansion and effector differentiation of TCF1 + CD8 + T cells within tumours, which promotes cancer immune escape. PGE 2 does not affect the priming of TCF1 + CD8 + T cells in draining lymph nodes. PGE 2 acts through EP 2 and EP 4 (EP 2 /EP 4 ) 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 EP 2 /EP 4 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 PGE 2 -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 PGE 2 -EP 2 /EP 4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
(© 2024. The Author(s).)
Databáze: MEDLINE
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