| Download | - View final version: Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy (PDF, 5.1 MiB)
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| DOI | Resolve DOI: https://doi.org/10.1016/j.xcrm.2024.101465 |
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| Author | Search for: St. Paul, MichaelORCID identifier: https://orcid.org/0000-0002-5213-6415; Search for: Saibil, Samuel D.; Search for: Kates, Meghan; Search for: Han, SeongJun; Search for: Lien, Scott C.; Search for: Laister, Rob C.; Search for: Hezaveh, Kebria; Search for: Kloetgen, Andreas; Search for: Penny, Susanne1; Search for: Guo, Tingxi; Search for: Garcia-Batres, Carlos; Search for: Smith, Logan K.; Search for: Chung, Douglas C.; Search for: Elford, Alisha R.; Search for: Sayad, Azin; Search for: Pinto, Devanand1ORCID identifier: https://orcid.org/0000-0002-0665-7041; Search for: Mak, Tak W.; Search for: Hirano, Naoto; Search for: McGaha, Tracy; Search for: Ohashi, Pamela S. |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Funder | Search for: Canadian Institutes of Health Research |
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| Format | Text, Article |
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| Subject | GCN2; halofuginone; adoptive cell therapy; immunotherapy; CD8⁺ T cell; autophagy; immunometabolism; 4-1BB |
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| Abstract | 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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| Publication date | 2024-03-08 |
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| Publisher | Cell Press |
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| Licence | |
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| Language | English |
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| Peer reviewed | Yes |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | e46d5009-0d34-4241-b10d-d7c647647522 |
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| Record created | 2024-06-18 |
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| Record modified | 2024-06-18 |
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