在固体但不是液体瘤中,需要IFNγR通路来杀死CAR T细胞
Rebecca C Larson1,2,3,4, Michael C Kann1,3, Stefanie R Bailey1,2,3
1Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Nature
|April 14, 2022
概括
化学抗原受体 (CAR) T 细胞治疗对血液癌症有效,但对固体瘤没有效果. 研究人员发现干扰素玛受体 (IFNγR) 信号传递对CAR T细胞杀死固体瘤细胞至关重要.
科学领域:
- 癌症学
- 免疫疗法
- 基因组学
背景情况:
- 化学抗原受体 (CAR) T细胞疗法彻底改变了血液恶性瘤的治疗方法.
- 然而,由于潜在的内在抗药机制,它对固体瘤的疗效仍然有限.
研究的目的:
- 使用全基因组的CRISPR淘汰屏幕系统地识别固体瘤中的耐药性途径.
- 研究干扰素玛受体 (IFNγR) 在CAR T细胞抗质母细胞瘤疗效中的作用.
主要方法:
- 在质母细胞细胞中进行全基因组CRISPR淘汰选.
- 在体外和体内评估CAR T细胞的细胞毒性.
- 使用转录特征来分析细胞反应.
主要成果:
- 在固体瘤中,IFNγR信号基因 (IFNGR1,JAK1,JAK2) 的丧失会对CAR T细胞产生抗药性,而非血液性恶性瘤.
- 缺少IFNγR1的质母细胞显示细胞粘附路径上调的减少和CAR T细胞结合的减少.
- 在质母细胞瘤中,IFNγR信号传递对CAR T细胞粘附和生产性细胞毒性至关重要.
结论:
- 固体瘤和液体瘤在与CAR T细胞的相互作用上有所不同.
- 在固体瘤中,IFNγR信号对CAR T细胞敏感性至关重要,独立于传统的抗原呈现.
- 增强CAR T细胞结合相互作用可能改善固体瘤的治疗结果.
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