通过CAR工程的淋巴细胞持久性是由FAS连接体/FAS自调节电路控制的
Fei Yi1, Tal Cohen1,2, Natalie Zimmerman1
1Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
bioRxiv : the preprint server for biology
|March 11, 2024
概括
CAR T和NK细胞的持久性受到FAS连接体 (FAS-L) 在T细胞,NK细胞和CAR细胞本身表达的限制. 阻断FAS-L可以改善CAR细胞的持久性,并增强抗瘤功效.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 癌症治疗 癌症治疗
背景情况:
- 化学抗原受体 (CAR) 工程的T和NK细胞对B细胞恶性瘤有希望,但面临有限的持久性.
- FAS连接体 (FAS-L) /FAS通路调节淋巴细胞稳态,但其在CAR细胞持久性中的作用尚不清楚.
研究的目的:
- 在癌症中识别表达FAS连接体 (FAS-L) 的细胞,并确定其对CAR T和NK细胞持久性的影响.
- 研究阻断FAS-L/FAS通路是否可以增强CAR细胞的持久性和抗瘤功效.
主要方法:
- 单细胞地图结构用于绘制不同癌症类型中FASLG基因表达的地图.
- 使用具有或没有主导负FAS受体 (ΔFAS) 的CAR T/NK细胞进行竞争性健身测定.
- FASLG淘汰实验和CAR介导瘤杀伤和抗瘤疗效的评估.
主要成果:
- 主要在内源性T细胞,NK细胞和CAR-T细胞中发现FASLG的表达,在瘤和树皮细胞中表达最小.
- 表达 ΔFAS 的 CAR T 和 NK 细胞表现出增强的持久性和组织丰富性,这被 FASLG 淘汰扭转.
- FASLG对于CAR介导的瘤杀死没有必要,但 ΔFAS 同表达改善了抗瘤疗效.
结论:
- 通过CAR设计的淋巴细胞持续性是由自调节的FAS-L/FAS电路调节的.
- 阻断FAS-L可以克服持久性限制,并提高CAR T和NK细胞疗法的疗效.
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