GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency
The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th<sub>17</sub> differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
Authors
- Jameel Lone (ORCID: https://orcid.org/0000-0003-4571-1335)
- Kara L. Davis (ORCID: https://orcid.org/0000-0002-7182-2592)
- Katrin J. Svensson (ORCID: https://orcid.org/0000-0001-5376-5128)
- Lucille Stuani (ORCID: https://orcid.org/0000-0001-6116-981X)
- Basil Michael (ORCID: https://orcid.org/0000-0003-4009-0912)
- Justin Arredondo-Guerrero (ORCID: https://orcid.org/0000-0003-1537-4825)
- Jing Huang (ORCID: https://orcid.org/0000-0002-0173-0342)
- Steven A. Feldman (ORCID: https://orcid.org/0000-0003-2098-3860)
- Meena Malipatlolla
- Carley Fowler (ORCID: https://orcid.org/0000-0003-3003-0174)
- Maya Kasowski (ORCID: https://orcid.org/0000-0001-6583-0759)
- Crystal L. Mackall (ORCID: https://orcid.org/0000-0001-6323-4304)
- Kévin Contrepois (ORCID: https://orcid.org/0000-0001-9678-5161)
- Elena Sotillo (ORCID: https://orcid.org/0000-0002-3993-1932)
- Shaurya Dhingra (ORCID: https://orcid.org/0000-0002-5327-7535)
- Malek Bashti (ORCID: https://orcid.org/0000-0003-0398-3367)
- Dorota D. Klysz (ORCID: https://orcid.org/0000-0002-6733-6110)
- Peng Xu (ORCID: https://orcid.org/0000-0002-7573-4813)
- Yiyun Chen (ORCID: https://orcid.org/0000-0003-3886-2100)
- Chris Fisher (ORCID: https://orcid.org/0000-0001-5884-4941)
- Audre May
Institutions
- Cardiovascular Institute of the South (US)
- Parker Institute for Cancer Immunotherapy (US)
- Stanford Medicine (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-06
- DOI
- https://doi.org/10.1038/s41467-024-52666-y
- Citations
- 73
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 20.63
Funders
- Virginia and D.K. Ludwig Fund for Cancer Research
- Blavatnik Family Foundation
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health