PuSH - Publication Server of Helmholtz Zentrum München: PGE<sub>2</sub> inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

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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.S.* ; 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.*

PGE₂ inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

Nature 629, 426-434 (2024)

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Expansion of antigen-experienced CD8⁺ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer¹. Interleukin-2 (IL-2) acts as a key regulator of CD8⁺ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability^2,3. 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 (PGE₂), a known negative regulator of immune response in the tumour microenvironment^4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8⁺ TILs via the PGE₂ receptors EP2 and EP4. Mechanistically, PGE₂ inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ_c chain, resulting in defective assembly of IL-2Rβ-IL2Rγ_c 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 PGE₂ 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 PGE₂ 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Tumor-infiltrating Lymphocytes; T-cells; Immunotherapy; Biogenesis; Activation; Therapy; Pathway

ISSN (print) / ISBN 0028-0836

e-ISSN 1476-4687

Journal Nature

Quellenangaben Volume: 629, Issue: 8011, Pages: 426-434

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)

Grants Center of Experimental Therapies (CTE)
Biltema Foundation
Paul Matson Foundation
Cancera Foundation
Swiss Cancer League Foundation
German Research Foundation (DFG)
Ludwig Institute for Cancer Research

PuSH - Publication Server of Helmholtz Zentrum München

PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

PGE₂ inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.