Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment
The efficacy of chimeric antigen receptor T cell (CAR-T) therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28 EGFRvIII gliomas revealed impaired mitochondrial ATP production and a markedly hypoxic status compared with ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of the AMPK activator metformin and the mTOR inhibitor rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-γ coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective antiglioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28 EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group, with fewer Ly6c+CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions under in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
JCI insight - 9(2024), 7 vom: 08. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hatae, Ryusuke [VerfasserIn] |
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| Links: |
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| Themen: |
AMP-Activated Protein Kinases |
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| Anmerkungen: |
Date Completed 09.04.2024 Date Revised 09.04.2024 published: Electronic UpdateOf: bioRxiv. 2023 Nov 15;:. - PMID 38014236 Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.177141 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a The efficacy of chimeric antigen receptor T cell (CAR-T) therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28 EGFRvIII gliomas revealed impaired mitochondrial ATP production and a markedly hypoxic status compared with ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of the AMPK activator metformin and the mTOR inhibitor rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-γ coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective antiglioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28 EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group, with fewer Ly6c+CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions under in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Brain cancer | |
| 650 | 4 | |a Cancer immunotherapy | |
| 650 | 4 | |a Hypoxia | |
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| 700 | 1 | |a Chen, Tiffany |e verfasserin |4 aut | |
| 700 | 1 | |a Phyu, Su |e verfasserin |4 aut | |
| 700 | 1 | |a Chuntova, Pavlina |e verfasserin |4 aut | |
| 700 | 1 | |a Nejo, Takahide |e verfasserin |4 aut | |
| 700 | 1 | |a Levine, Lauren S |e verfasserin |4 aut | |
| 700 | 1 | |a Spitzer, Matthew H |e verfasserin |4 aut | |
| 700 | 1 | |a Okada, Hideho |e verfasserin |4 aut | |
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