GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency

Justin A. Guerrero, Dorota D. Klysz, Yiyun Chen, Meena Malipatlolla, Jameel Lone, Carley Fowler, Lucille Stuani, Audre May, Malek Bashti, Peng Xu, Jing Huang, Basil Michael, Kévin Contrepois, Shaurya Dhingra, Chris Fisher, Katrin J. Svensson, Kara L. Davis, Maya Kasowski, Steven A. Feldman, Elena Sotillo () and Crystal L. Mackall ()
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Justin A. Guerrero: Stanford University School of Medicine
Dorota D. Klysz: Stanford University School of Medicine
Yiyun Chen: Stanford University School of Medicine
Meena Malipatlolla: Stanford University School of Medicine
Jameel Lone: Stanford University School of Medicine
Carley Fowler: Stanford University School of Medicine
Lucille Stuani: Stanford University School of Medicine
Audre May: Stanford University School of Medicine
Malek Bashti: Stanford University School of Medicine
Peng Xu: Stanford University School of Medicine
Jing Huang: Stanford University School of Medicine
Basil Michael: Stanford University School of Medicine
Kévin Contrepois: Stanford University School of Medicine
Shaurya Dhingra: Stanford University School of Medicine
Chris Fisher: Stanford University School of Medicine
Katrin J. Svensson: Stanford University School of Medicine
Kara L. Davis: Stanford University School of Medicine
Maya Kasowski: National Cancer Institute
Steven A. Feldman: Stanford University School of Medicine
Elena Sotillo: Stanford University School of Medicine
Crystal L. Mackall: Stanford University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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 Th17 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.

Date: 2024
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DOI: 10.1038/s41467-024-52666-y

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