Contributors: Institut Cochin (IC UM3 (UMR 8104 / U1016)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE); Université de Caen Normandie (UNICAEN); Normandie Université (NU)-Normandie Université (NU)-CHU Caen; Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse Caen (UNICANCER/CRLC); Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM); Institut Cochin Departement Infection, immunité, inflammation; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)); École Pratique des Hautes Études (EPHE); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité); This work was partially supported by the European Union’sHorizon 2020 research and innovation programme under the Marie-Skłodowska Curie grant agreement No. 945298 “ParisRegionFP” (LS), the French “Ligue Nationale contre le Cancer” (Equipes labellisées, ED), GeFluc Ile-De-France (Call 2021 & Call 2023, LS), European Union’s Horizon Europe programme (HE-MSCA-PF 101062302, LS), and Fondation ARC (PDF2 ARCPDF22020010001123, LS). LS and MCAG were also supported by a grant from Institut Cochin (PIC 2022). MF and DA were respectively supported by “LigueNationale contre le Cancer” and “China Scholarship Council” PhD fellowships.We are extremely thankful tomembers of the Cochin Institute Imaging (IMAG’IC), Cytometry and ImmunoBiology (CYBIO) and In vivo Imaging (PIV) facilities for their help and support in performing microscopy, flow cytometry and animal experiments,respectively.
نبذة مختصرة : International audience ; The ability of CD8 + T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8 + T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8 + T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8 + T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8 + T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.
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