通过破坏SKI-SMAD2/3轴来增强收养T细胞疗法,以抵消TGF-β介导的免疫抑制
Xiaohan Jin1, Jingxuan Yu2, Xinyu Wu3
1Institute of Basic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China; School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
概括
转化生长因子β (TGF-β) 阻塞通过预防T细胞功能障碍来增强抗瘤免疫力. 在T细胞中通过SKImut2/3工程恢复SKI表达,可以克服TGF-β诱导的免疫抑制,在临床前模型中改善癌细胞的杀死和生存.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 癌症治疗 癌症治疗
背景情况:
- 转化生长因子β (TGF-β) 是瘤微环境中的一个关键的免疫抑制细胞因子.
- TGF-β抑制T细胞介导的抗瘤免疫力的确切机制尚未完全理解.
- 目前针对TGF-β信号的策略在增强T细胞功能方面存在局限性.
研究的目的:
- 阐明转录共抑制剂SKI在TGF-β诱导的T细胞功能障碍中的作用.
- 开发一种新的治疗策略,通过克服TGF-β介导免疫抑制来增强基于T细胞的癌症免疫疗法.
- 在临床前癌症模型中评估表达SMAD2/3结合缺陷SKI突变体 (SKImut2/3) 的工程T细胞的疗效.
主要方法:
- 使用蛋白质组分析研究了TGF-β信号组件 (SMAD2/3) 和SKI之间的相互作用.
- 工程化基因组抗原受体 (CAR) -T细胞和T细胞受体 (TCR) -T细胞以表达野生型SKI或SKImut2/3.3.
- 在体外TGF-β刺激下评估T细胞激活,细胞因子生产和瘤细胞杀伤能力.
- 在固体和液体瘤的小鼠模型中评估了SKImut2/3工程T细胞的治疗疗效.
主要成果:
- TGF-β刺激诱导SMAD2/3与SKI的相互作用,导致SKI的蛋白质体降解和T细胞功能受损.
- 通过防止SKI降解,表达SKImut2/3的工程T细胞抵抗了TGF-β介导的免疫抑制.
- 在实验室中,SKImut2/3转换的CAR-T细胞表现出增强的激活,细胞因子的产生和优异的癌细胞杀死.
- 在T细胞疗法中SKImut2/3表达在液体和固体瘤的临床前模型中延长了生存期.
结论:
- SKI降解是TGF-β抑制T细胞抗瘤免疫力的关键机制.
- 工程T细胞表达SKImut2/3代表了一种有前途的策略,以提高T细胞基础的癌症免疫疗法的疗效和耐久性.
- 基于SKImut2/3的治疗有可能改善各种癌症类型的治疗结果.
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