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通过逆转TGF-β信号,在免疫抑制性瘤微环境中增强CAR-T细胞功能

Shen Zheng¹, Xuan Che¹, Kai Zhang²

¹Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing 100191, China.

Molecular therapy : the journal of the American Society of Gene Therapy

|December 14, 2024

概括

这项研究引入了一种新的化学抗原受体 (CAR) T细胞疗法,通过阻断转化生长因子-β (TGF-β) 和增强T细胞功能来克服免疫抑制性瘤微环境,用于固体瘤治疗.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
生物技术是生物技术.

背景情况:

固体瘤中的瘤微环境通常会抑制嵌合抗原受体 (CAR) T细胞活动.
转化生长因子-β (TGF-β) 是一种关键的免疫抑制细胞因子,限制了CAR T细胞的持久性和功能.
现有的TGF-β阻断策略在固体瘤中有效性有限.

研究的目的:

开发一种使用逆转细胞因子受体 (ICR) 的新型CAR T细胞策略,以克服TGF-β介导的免疫抑制.
在固体瘤中增强CAR T细胞持久性和抗瘤功效.
为了证明ICRs在工程中的潜力,采用了具有新功能的T细胞.

主要方法:

工程CAR T细胞具有仿真ICR结构 (TB15) 融合TGF-β受体II细胞外域和IL-15受体α细胞质域.
向表皮生长因子受体 (EGFR) 瘤抗原.
在高TGF-β固体瘤的小鼠模型中的体内研究.

主要成果:

信号逆转的CAR/TB15T细胞有效地阻断了瘤微环境中的TGF-β信号传递.
重新定位的IL-15信号增强了CAR T细胞的持久性和功能.
在小鼠中证明有效的瘤治疗,验证了新的策略.

结论:

新的ICR修饰的CAR T细胞策略提供了一种有希望的方法来克服免疫抑制瘤微环境.
这种方法通过同时阻断TGF-β和激活IL-15信号来提高CAR T细胞的疗效.
扩展了合成受体信号传递的范围,超出了直接杀死范围,为工程T细胞对抗固体瘤提供了一个新的平台.

关键词:

在CAR-T细胞中.免疫抑制性瘤微环境介质蛋白-15 介质蛋白-15 反向细胞因子受体的反向细胞因子受体转化生长因子β的转化生长因子β.

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