Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Nat Commun. 2024 Oct 6;15(1):8658. doi: 10.1038/s41467-024-52666-y.
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 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.
T 细胞激活和增殖所需的密集营养需求，加上肿瘤微环境中营养物质的竞争，使得葡萄糖的可用性可能会限制 CAR-T 细胞的功能。在这里，我们试图检验这样一个假设，即在原代人 CAR-T 细胞中稳定过表达（OE）葡萄糖转运蛋白 GLUT1 会改善它们的功能和抗肿瘤效力。我们观察到，CAR-T 细胞中的 GLUT1OE 增加了葡萄糖消耗、糖酵解、糖酵解储备和氧化磷酸化，这些效应与 T 细胞耗竭减少和 Th 分化增加有关。GLUT1OE 还诱导与谷胱甘肽介导的抵抗活性氧增加以及肌苷积累增加相关的广泛代谢重编程。当受到肿瘤的挑战时，GLUT1OE CAR-T 细胞分泌更多的促炎细胞因子，并在体外显示出增强的细胞毒性，在小鼠模型中表现出更好的肿瘤控制和持久性。我们的综合研究结果支持这样一种观点，即葡萄糖的可用性是效应 CAR-T 细胞功能的限速因素，并表明通过 GLUT1OE 增加葡萄糖的可用性可以增强抗肿瘤免疫功能。
