Nature Communications (Oct 2024)

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,
  • Crystal L. Mackall

DOI
https://doi.org/10.1038/s41467-024-52666-y
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 20

Abstract

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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.