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在CAR-T细胞中的SMAD7表达改善了固体瘤的持续性和安全性

Sixin Liang^1,2, Rui Zheng¹, Baile Zuo^1,2

¹State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.

Cellular & molecular immunology

|January 4, 2024

概括

与仿真抗原受体T (CAR-T) 细胞共同表达SMAD7,通过防止疲劳和减少有害细胞因子的释放,提高CAR-T疗法的疗效和安全性,提高它们对抗固体瘤的能力.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
细胞疗法细胞疗法

背景情况:

化学抗原受体T (CAR-T) 细胞疗法在血液癌症中表现有前途,但在固体瘤中面临挑战.
T细胞耗尽和细胞因子释放综合征限制了CAR-T在固体瘤中的有效性和安全性.
转化生长因子-β (TGF-β) 在瘤微环境 (TME) 中驱动免疫抑制和细胞因子生产.

研究的目的:

研究T细胞中与HER2向的CAR共同表达SMAD7的潜力,以克服TME诱导的疲劳并降低毒性.
在固体瘤模型中评估SMAD7对CAR-T细胞功能,细胞因子产生和抗瘤活性的影响.

主要方法:

产生了工程T细胞,共同表达HER2向的CAR和SMAD7.
评估了细胞分解功效,抗对TGF-β诱导的疲劳,和细胞因子的产生.
在患者衍生瘤器官中评估了CAR-T细胞透和激活.
在面临瘤挑战的小鼠中,监测瘤生长抑制和存活率.

主要成果:

经SMAD7工程的CAR-T细胞表现出增强的细胞分解活性和抵抗TGF-β诱导的疲劳.
SMAD7显著降低了CAR-T细胞的炎症性细胞因子产生.
SMAD7降低了TGF-β受体I的调节,破坏了TGF-β和NF-κB通路的交叉.
这些CAR-T细胞表现出持续的瘤抑制,在小鼠中改善了生存率,并增强了瘤器官的透.

结论:

与CAR-T细胞同时表达SMAD7是一种可行的策略,可以提高固体瘤治疗的疗效和安全性.
SMAD7减轻T细胞耗尽和全身毒性,克服免疫抑制的TME.
这种方法有望改善CAR-T细胞疗法,挑战固体瘤的指示.

关键词:

使用CAR-T细胞治疗.细胞因子释放综合征 (CRS)通过NF-κB路径.在SMAD7中,SMAD7在SMAD7中使用了SMAD7.在TGF-β路径中.

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