In this study, Guerrero and Klysz et al. stably overexpressed (OE) the glucose transporter GLUT1 in primary human CAR-T cells to determine if enhancing glucose availability would improve their function and antitumor potency. GLUT1OE in CAR-T cells enhanced glycolysis and oxidative phosphorylation, and was associated with decreased T cell exhaustion, increased Th17 differentiation, and increased glutathione-mediated resistance to ROS. In tumor-challenged mice, GLUT1OE CAR-T cells secreted more proinflammatory cytokines, and demonstrated superior tumor cell clearance and persistence compared to control CAR-T cells.
Contributed by Katherine Turner
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 Th(17) 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.
Author Info: (1) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (2) Center for Cancer Cell Therapy, Stanford Cancer Institu
Author Info: (1) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (2) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (3) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (4) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (5) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (6) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (7) Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (8) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (9) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (10) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (11) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (12) Metabolic Health Center, Stanford University School of Medicine, Stanford, CA, USA. (13) Metabolic Health Center, Stanford University School of Medicine, Stanford, CA, USA. (14) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (15) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (16) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. (17) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (18) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Department of Genetics, Stanford University, Stanford, CA, USA. Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA. Division of Bone Marrow Transplant-Cell Therapy, Dept of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. (20) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. esotillo@stanford.edu. (21) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA. cmackall@stanford.edu. Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Division of Bone Marrow Transplant-Cell Therapy, Dept of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cmackall@stanford.edu.
