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在CAR-T细胞中GLUT1的过度表达诱导了代谢重编程,并增强了功效

Justin A Guerrero¹, Dorota D Klysz¹, Yiyun Chen¹

¹Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, tanford, CA, USA.

Nature communications

|October 6, 2024

概括

在CAR-T细胞中增强葡萄糖运输体GLUT1可以提高它们的抗瘤能力. 在模型中,过度表达GLUT1可以改善T细胞功能,对抗疲劳,并增加瘤控制.

科学领域:

免疫学免疫学免疫学
代谢工程是代谢工程.
癌症治疗癌症治疗

背景情况:

激活T细胞需要大量的营养素,而这些营养素在瘤微环境中通常是稀缺的.
葡萄糖的可用性可能会限制CAR-T细胞治疗癌症的有效性.

研究的目的:

测试葡萄糖载体GLUT1的稳定过度表达是否增强CAR-T细胞功能和抗瘤功效.
研究GLUT1过度表达在CAR-T细胞中的代谢和功能后果.

主要方法:

生成的初级人类CAR-T细胞具有稳定的GLUT1过度表达 (GLUT1OE).
评估细胞代谢 (葡萄糖消耗,糖解,氧化酸化) 和T细胞表型 (耗尽,分化).
在小鼠模型中评估了体外细胞毒性和体外瘤控制和持续性.

主要成果:

GLUT1OE CAR-T细胞显示葡萄糖吸收,糖解和氧化酸化的增加.
过度表达导致T细胞疲劳减少,增强了Th17分化,并增加了对氧化应激的抵抗力.
GLUT1OE CAR-T细胞表现出改善的促炎性细胞因子分泌,增强的体外细胞毒性,以及优越的瘤控制和持续性.

结论:

葡萄糖的可用性是有效因子CAR-T细胞功能的速度限制因素.
通过GLUT1过度表达来增强葡萄糖吸收可以显著增加CAR-T细胞抗瘤免疫力和治疗潜力.

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