FOXO1是CAR T内存编程的主调节器
Alexander Doan1, Katherine P Mueller2,3,4,5,6, Andy Chen7,8,9
1Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Research square
|November 21, 2023
概括
转录因子FOXO1促进记忆程序,并防止CAR T细胞的耗尽,增强其持久性和抗瘤活性. 这一发现为改善CAR T细胞疗法提供了新的策略.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
背景情况:
- 卡尔-T细胞治疗的持续性有限,阻碍了B细胞恶性瘤和固体瘤的治疗.
- 像TCF7 (TCF1) 一样,记忆基因表达对于CAR T细胞的反应和长期持续性至关重要.
- 了解CAR T细胞记忆和疲劳的调节者对于提高治疗疗效至关重要.
研究的目的:
- 研究先驱转录因子FOXO1在促进记忆程序和防止人类CAR T细胞疲劳中的作用.
- 为了确定FOXO1是否可以被利用来增强CAR T细胞的持久性和抗瘤活性.
主要方法:
- 在人类CAR T细胞中对FOXO1进行药理抑制和基因编辑.
- 在CAR T细胞中过度表达FOXO1和TCF1.
- 在体外和体内评估基因表达,表观遗传变化 (染色质可访问性),细胞表型,代谢适应性和抗瘤活性.
- 关联内源性FOXO1活性与患者对CAR T和TIL疗法的反应.
主要成果:
- 药物抑制或基因编辑FOXO1损害记忆基因表达,诱导疲劳,并减少抗瘤活性.
- 过度表达FOXO1增强了T细胞记忆基因表达,增加了染色质可访问性,并改善了CAR T细胞功能,记忆潜力,代谢适应性,以及体内持久性和抗瘤活性.
- 过度表达TCF1并没有强制执行记忆程序或改善CAR T细胞功效.
- 内源FOXO1活性与患者对CAR T和TIL疗法的反应相关.
结论:
- FOXO1作为一个关键的先驱转录因子,促进记忆程序,并抑制人类CAR T细胞的疲劳.
- 通过FOXO1介导的记忆重编程可以显著提高CAR T细胞在癌症免疫治疗中的持久性和功效.
- 针对像FOXO1这样的先驱因素是优化治疗T细胞状态和改善临床结果的有希望的策略.
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