抗体和CAR介导的巨细胞细胞毒性的可利用机制
Tianyi Liu1,2, Meng Zhang1,2, Tatyanah Farsh1,2
1University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA.
Nature communications
|July 2, 2025
概括
自基因ATG9A调节癌细胞对巨细胞杀死的防御. 抑制ATG9A增强了癌细胞对巨细胞媒介死亡的敏感性,在与CSF1R抑制剂相结合时改善了抗瘤免疫力.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 细胞生物学 细胞生物学
背景情况:
- 巨细胞是瘤中的关键免疫细胞,影响癌细胞的生存或死亡.
- 巨细胞中介性细胞毒性对抗瘤免疫至关重要,但其调节因子尚未完全理解.
研究的目的:
- 为了确定巨细胞对癌细胞的细胞毒性的调节者.
- 探索结合基于巨细胞的疗法与瘤内在机制的治疗策略.
主要方法:
- 在与CAR巨细胞共同培养系统中利用CRISPR屏幕.
- 在ATG9A枯竭的癌细胞进行了体外和体内实验.
- 进行了蛋白质组和脂质组分析.
- 在小鼠模型中研究了涉及CSF1R抑制和ATG9A调节的组合疗法.
主要成果:
- 自基因ATG9A被确定为癌细胞抵抗巨细胞杀死的关键调节者.
- 癌细胞中的ATG9A缺乏使它们对巨细胞诱导的死亡敏感.
- 缺少ATG9A会损害癌细胞膜修复机制,包括 lysosomal exocytosis,ceramide生产和洞穴内细胞.
- 联合抑制CSF1R (丰富细胞毒性巨细胞) 和ATG9A介导的瘤膜修复增强了小鼠的抗瘤抗体疗效.
结论:
- 巨细胞毒性对于CAR巨和基于抗体的治疗中瘤消除至关重要.
- 向ATG9A以损害瘤膜修复,特别是与增强细胞毒性巨细胞群的策略相结合时,可以显著提高癌症免疫疗法的疗效.
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