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Rab5克服了由瘤介导的CAR捕获引起的CAR T细胞功能障碍

Meidi Gu, Edmund J Carvalho, Kaitlin A Read

bioRxiv : the preprint server for biology

|August 30, 2024

概括

瘤细胞可以内化化学抗原受体 (CAR) T 细胞,导致CAR T 细胞功能障碍. 过度表达Rab5可以防止这种"CAR-jacking",维持CAR-T细胞的功能并增强瘤清除.

科学领域:

免疫治疗是一种免疫疗法.
细胞生物学细胞生物学
癌症研究癌症研究

背景情况:

化学抗原受体 (CAR) T细胞疗法面临的挑战是由于持续的瘤相互作用,T细胞功能障碍和瘤脱离.
瘤细胞可以内化CAR分子,导致表面CAR的丧失和T细胞杀死能力受损.

研究的目的:

调查Rab5在预防由CAR分子内部化引起的CAR T细胞功能障碍中的作用.
探索Rab5在增强CAR T细胞活性和对固体瘤的治疗疗效方面的潜力.

主要方法:

在CAR T细胞中过度表达Rab5.
评估克拉斯林独立内细胞和CAR表面表达的评估.
膜突起和T细胞细胞分解活性的分析.
在体内研究中,使用具有表达美索林的固体癌症的人性化小鼠.

主要成果:

Rab5过度表达增强了克拉特林独立的内细胞分裂,防止了T细胞表面的CAR损失.
在重复的瘤挑战后,Rab5在CAR T细胞上保持了膜突起,与有效的瘤清除相关.
通过保持CAR表面表达,Rab5表达的CAR T细胞表现出更好的活性,并通过维持CAR表面表达在体内清除耐火固体瘤.

结论:

Rab5通过抑制"CAR-jacking"和促进CAR内细胞循环,防止CAR T细胞功能障碍.
Rab5表达增强了CAR T细胞对固体瘤的治疗疗效,表明其潜在的临床实用性.

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