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PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
Lacher, Sebastian B; Dörr, Janina; de Almeida, Gustavo P; Hönninger, Julian; Bayerl, Felix; Hirschberger, Anna; Pedde, Anna-Marie; Meiser, Philippa; Ramsauer, Lukas; Rudolph, Thomas J; Spranger, Nadine; Morotti, Matteo; Grimm, Alizee J; Jarosch, Sebastian; Oner, Arman; Gregor, Lisa; Lesch, Stefanie; Michaelides, Stefanos; Fertig, Luisa; Briukhovetska, Daria; Majed, Lina; Stock, Sophia; Busch, Dirk H; Buchholz, Veit R; Knolle, Percy A; Zehn, Dietmar; Dangaj Laniti, Denarda; Kobold, Sebastian; Böttcher, Jan P.
Afiliación
  • 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.
  • Bayerl F; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, 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; Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
  • Grimm AJ; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.
  • Jarosch S; Department of Oncology, University Hospital of Lausanne (CHUV) and UNIL, Lausanne, Switzerland.
  • Oner A; Agora Cancer Research Center, Lausanne, Switzerland.
  • Gregor L; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.
  • Lesch S; Department of Oncology, University Hospital of Lausanne (CHUV) and UNIL, Lausanne, Switzerland.
  • Michaelides S; Agora Cancer Research Center, Lausanne, Switzerland.
  • Fertig L; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine and Health, TUM, Munich, Germany.
  • Briukhovetska D; Boehringer Ingelheim, Biberach, 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.
  • Busch DH; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.
  • Buchholz VR; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.
  • Knolle PA; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.
  • Zehn 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.
  • Dangaj Laniti 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.
  • 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.
  • Böttcher JP; Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany.
Nature ; 629(8011): 417-425, 2024 May.
Article en En | MEDLINE | ID: mdl-38658748
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre / Dinoprostona / Linfocitos Infiltrantes de Tumor / Linfocitos T CD8-positivos / Escape del Tumor / Proliferación Celular / Neoplasias Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre / Dinoprostona / Linfocitos Infiltrantes de Tumor / Linfocitos T CD8-positivos / Escape del Tumor / Proliferación Celular / Neoplasias Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido