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

Matteo Morotti, Alizee J. Grimm, Helen Carrasco Hope, Marion Arnaud, Mathieu Desbuisson, Nicolas Rayroux, David Barras, Maria Masid, Baptiste Murgues, Bovannak S. Chap, Marco Ongaro, Ioanna A. Rota, Catherine Ronet, Aspram Minasyan, Johanna Chiffelle, Sebastian B. Lacher, Sara Bobisse, Clément Murgues, Eleonora Ghisoni, Khaoula Ouchen, Ribal Bou Mjahed, Fabrizio Benedetti, Naoill Abdellaoui, Riccardo Turrini, Philippe O. Gannon, Khalil Zaman, Patrice Mathevet, Loic Lelievre, Isaac Crespo, Marcus Conrad, Gregory Verdeil, Lana E. Kandalaft, Julien Dagher, Jesus Corria-Osorio, Marie-Agnes Doucey, Ping-Chih Ho, Alexandre Harari, Nicola Vannini, Jan P. Böttcher, Denarda Dangaj Laniti () and George Coukos ()
Additional contact information
Matteo Morotti: University of Lausanne (UNIL)
Alizee J. Grimm: University of Lausanne (UNIL)
Helen Carrasco Hope: University of Lausanne (UNIL)
Marion Arnaud: University of Lausanne (UNIL)
Mathieu Desbuisson: University of Lausanne (UNIL)
Nicolas Rayroux: University of Lausanne (UNIL)
David Barras: University of Lausanne (UNIL)
Maria Masid: University of Lausanne (UNIL)
Baptiste Murgues: University of Lausanne (UNIL)
Bovannak S. Chap: University of Lausanne (UNIL)
Marco Ongaro: University of Lausanne (UNIL)
Ioanna A. Rota: University of Lausanne (UNIL)
Catherine Ronet: University of Lausanne (UNIL)
Aspram Minasyan: University of Lausanne (UNIL)
Johanna Chiffelle: University of Lausanne (UNIL)
Sebastian B. Lacher: Technical University of Munich (TUM)
Sara Bobisse: University of Lausanne (UNIL)
Clément Murgues: Lausanne University Hospital (CHUV)
Eleonora Ghisoni: University of Lausanne (UNIL)
Khaoula Ouchen: University of Lausanne (UNIL)
Ribal Bou Mjahed: University of Lausanne (UNIL)
Fabrizio Benedetti: University of Lausanne (UNIL)
Naoill Abdellaoui: University of Lausanne (UNIL)
Riccardo Turrini: University of Lausanne (UNIL)
Philippe O. Gannon: Lausanne University Hospital (CHUV)
Khalil Zaman: Lausanne University Hospital (CHUV) and University of Lausanne
Patrice Mathevet: Lausanne University Hospital (CHUV)
Loic Lelievre: Lausanne University Hospital (CHUV)
Isaac Crespo: University of Lausanne (UNIL)
Marcus Conrad: Helmholtz Munich
Gregory Verdeil: University of Lausanne (UNIL)
Lana E. Kandalaft: Lausanne University Hospital (CHUV)
Julien Dagher: Lausanne University Hospital (CHUV)
Jesus Corria-Osorio: University of Lausanne (UNIL)
Marie-Agnes Doucey: University of Lausanne (UNIL)
Ping-Chih Ho: University of Lausanne (UNIL)
Alexandre Harari: University of Lausanne (UNIL)
Nicola Vannini: University of Lausanne (UNIL)
Jan P. Böttcher: Technical University of Munich (TUM)
Denarda Dangaj Laniti: University of Lausanne (UNIL)
George Coukos: University of Lausanne (UNIL)

Nature, 2024, vol. 629, issue 8011, 426-434

Abstract: Abstract 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 capability2,3. 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 microenvironment4,5, 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-2Rγc chain, resulting in defective assembly of IL-2Rβ–IL2Rγc 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.

Date: 2024
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DOI: 10.1038/s41586-024-07352-w

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