| Téléchargement | - Voir la version finale : Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy (PDF, 5.1 Mio)
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| DOI | Trouver le DOI : https://doi.org/10.1016/j.xcrm.2024.101465 |
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| Auteur | Rechercher : St. Paul, MichaelIdentifiant ORCID : https://orcid.org/0000-0002-5213-6415; Rechercher : Saibil, Samuel D.; Rechercher : Kates, Meghan; Rechercher : Han, SeongJun; Rechercher : Lien, Scott C.; Rechercher : Laister, Rob C.; Rechercher : Hezaveh, Kebria; Rechercher : Kloetgen, Andreas; Rechercher : Penny, Susanne1; Rechercher : Guo, Tingxi; Rechercher : Garcia-Batres, Carlos; Rechercher : Smith, Logan K.; Rechercher : Chung, Douglas C.; Rechercher : Elford, Alisha R.; Rechercher : Sayad, Azin; Rechercher : Pinto, Devanand1Identifiant ORCID : https://orcid.org/0000-0002-0665-7041; Rechercher : Mak, Tak W.; Rechercher : Hirano, Naoto; Rechercher : McGaha, Tracy; Rechercher : Ohashi, Pamela S. |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Bailleur de fonds | Rechercher : Canadian Institutes of Health Research |
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| Format | Texte, Article |
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| Sujet | GCN2; halofuginone; adoptive cell therapy; immunotherapy; CD8⁺ T cell; autophagy; immunometabolism; 4-1BB |
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| Résumé | The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8⁺ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8⁺ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8⁺ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity. |
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| Date de publication | 2024-03-08 |
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| Maison d’édition | Cell Press |
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| Licence | |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | e46d5009-0d34-4241-b10d-d7c647647522 |
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| Enregistrement créé | 2024-06-18 |
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| Enregistrement modifié | 2024-06-18 |
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