PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
Détails
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Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_5FCB44D6E4AA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
Périodique
Nature
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Statut éditorial
Publié
Date de publication
05/2024
Peer-reviewed
Oui
Volume
629
Numéro
8011
Pages
426-434
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Publication Status: ppublish
Résumé
Expansion of antigen-experienced CD8 <sup>+</sup> T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer <sup>1</sup> . Interleukin-2 (IL-2) acts as a key regulator of CD8 <sup>+</sup> cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability <sup>2,3</sup> . Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE <sub>2</sub> ), a known negative regulator of immune response in the tumour microenvironment <sup>4,5</sup> , is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 <sup>+</sup> TILs via the PGE <sub>2</sub> receptors EP2 and EP4. Mechanistically, PGE <sub>2</sub> inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ <sub>c</sub> chain, resulting in defective assembly of IL-2Rβ-IL2Rγ <sub>c</sub> membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE <sub>2</sub> signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE <sub>2</sub> in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Mots-clé
Animals, Humans, Mice, CD8-Positive T-Lymphocytes/cytology, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Cell Proliferation, Dinoprostone/metabolism, Down-Regulation, Ferroptosis, Interleukin Receptor Common gamma Subunit/biosynthesis, Interleukin Receptor Common gamma Subunit/deficiency, Interleukin Receptor Common gamma Subunit/metabolism, Interleukin-2/antagonists & inhibitors, Interleukin-2/immunology, Interleukin-2/metabolism, Interleukin-2 Receptor beta Subunit/metabolism, Lymphocytes, Tumor-Infiltrating/cytology, Lymphocytes, Tumor-Infiltrating/immunology, Lymphocytes, Tumor-Infiltrating/metabolism, Mitochondria/metabolism, Oxidative Stress, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism, Receptors, Prostaglandin E, EP2 Subtype/metabolism, Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors, Receptors, Prostaglandin E, EP4 Subtype/metabolism, Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors, Signal Transduction, TOR Serine-Threonine Kinases/metabolism, Tumor Microenvironment/immunology
Pubmed
Web of science
Open Access
Oui
Création de la notice
29/04/2024 8:17
Dernière modification de la notice
20/08/2024 6:23