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Hsc70通过向PD-L1以进行溶酶体降解来促进抗瘤免疫力

Xiaoyan Xu¹, Tingxue Xie^1,2, Mengxin Zhou^1,2

¹Research Center of Clinical Pharmacy of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.

Nature communications

|May 18, 2024

概括

热冲击相关蛋白70 (Hsc70) 促进编程细胞死亡连接体1 (PD-L1) 降解,减少其细胞表面循环. 抑制Hsc70或使用AUY-922可以增强抗瘤免疫力和免疫疗法的有效性.

科学领域:

免疫学免疫学免疫学
分子生物学分子生物学
癌症研究癌症研究

背景情况:

针对PD-1/PD-L1通路的免疫检查点抑制剂是关键的癌症疗法.
对这些疗法的耐药性可能来自PD-L1内部化和回收.
lysosome介导的PD-L1降解对于防止其膜回收来说至关重要.

研究的目的:

阐明Hsc70在PD-L1降解和回收中的作用.
确定针对Hsc70进行增强癌症免疫治疗的治疗策略.

主要方法:

研究了Hsc70对通过内体-溶解体通路的PD-L1降解的影响.
研究了Hsc70,PD-L1和CMTM6.1之间的相互作用.
使用一种Hsp90α/β抑制剂 (AUY-922) 来调节Hsc70表达和PD-L1水平.
评估了Hsc70调制和AUY-922对小鼠瘤生长和抗瘤免疫力的影响.

主要成果:

Hsc70通过内体-溶解体通路促进PD-L1降解,减少PD-L1的循环.
Hsc70与PD-L1的结合抑制了CMTM6-PD-L1的相互作用,促进了降解.
AUY-922治疗增加了Hsc70的表达,导致PD-L1 lysosomal降解的增强.
Hsc70过度表达或AUY-922治疗减少PD-L1表达,抑制瘤生长,并增强抗瘤免疫力.
AUY-922与抗PD-L1和抗CTLA4疗法协同作用,以提高抗瘤疗效.

结论:

Hsc70是PD-L1 lysosomal降解的关键调节者.
针对Hsc70介导的PD-L1降解提供了一种新的策略,以克服癌症免疫治疗中的抗性.
AUY-922 是一种潜在的治疗剂,可以增强现有免疫疗法的有效性.

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