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

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_5FCB44D6E4AA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
Journal
Nature
Author(s)
Morotti M., Grimm A.J., Hope H.C., Arnaud M., Desbuisson M., Rayroux N., Barras D., Masid M., Murgues B., Chap B.S., Ongaro M., Rota I.A., Ronet C., Minasyan A., Chiffelle J., Lacher S.B., Bobisse S., Murgues C., Ghisoni E., Ouchen K., Bou Mjahed R., Benedetti F., Abdellaoui N., Turrini R., Gannon P.O., Zaman K., Mathevet P., Lelievre L., Crespo I., Conrad M., Verdeil G., Kandalaft L.E., Dagher J., Corria-Osorio J., Doucey M.A., Ho P.C., Harari A., Vannini N., Böttcher J.P., Dangaj Laniti D., Coukos G.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
05/2024
Peer-reviewed
Oui
Volume
629
Number
8011
Pages
426-434
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Abstract
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.
Keywords
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
Yes
Create date
29/04/2024 8:17
Last modification date
20/08/2024 6:23
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