在CAR T细胞中过度表达会诱导抗疲劳性
Rachel C Lynn1,2, Evan W Weber1, Elena Sotillo1
1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Nature
|December 6, 2019
概括
化学抗原受体 (CAR) T 细胞耗尽限制了癌症治疗的有效性. 在CAR T细胞中增强转录因子c- Jun可以改善它们的抗瘤活性,并克服疲劳.
科学领域:
- 免疫学
- 癌症生物学
- 细胞疗法
背景情况:
- 化学抗原受体 (CAR) T 细胞在癌症治疗中表现有前途,但由于 T 细胞疲劳而受到限制.
- T细胞耗尽会降低CAR T细胞的抗瘤效果,这对其治疗应用构成重大障碍.
研究的目的:
- 研究人类CAR T细胞疲劳的生物学机制.
- 确定设计耐疲劳的CAR T细胞的策略,并增强它们的抗瘤功效.
主要方法:
- 使用具有强度信号的CAR模型系统来诱导人类T细胞的疲劳特征.
- 分析了与T细胞耗尽相关的基因表达,染色质可访问性和转录因子活性.
- 改造了CAR T细胞以过度表达AP-1转录因子c-Jun.
主要成果:
- CAR T 细胞耗尽与IL-2 生产受损和转录因子活性变化 (AP-1,bZIP,IRF) 有关.
- 在CAR T细胞中过度表达导致扩张,功能改善和终端分化减少.
- 在五种不同的小鼠模型中,改造的CAR T细胞表现出卓越的抗瘤功效.
结论:
- 在c-Jun的功能缺陷有助于在人体疲T细胞中观察到的功能障碍.
- 设计CAR-T细胞过度表达c-Jun使其抗疲劳,从而增强其治疗潜力.
- 通过c-Jun增强克服CAR-T细胞耗尽是这种新兴癌症治疗的关键障碍.
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