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E-twenty-six-specific序列变异5 (ETV5) 通过增强多态核髓衍生抑制细胞 (PMN-MDSC) 介导的免疫抑制促进肝细胞癌的进展和转移

Zerui Zhang¹, Wenjie Huang², Dian Hu¹

¹Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China.

|February 27, 2025

概括

甲状腺至甲状腺转变因子ETV5通过招募免疫抑制性髓状细胞促进肝细胞癌 (HCC) 转移和免疫逃避. 用ETV5准S100A9或PD-L1为HCC提供了一个有前途的组合疗法.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

肝细胞癌 (HCC) 免疫微环境的理解对于有效治疗至关重要.
免疫检查点封锁显示成功,但由于对HCC免疫格局的不完全了解,局限性仍然存在.

研究的目的:

调查E-26特定序列变异5 (ETV5) 在调节HCC免疫微环境中的作用.
阐明ETV5影响HCC进展和免疫逃避的机制.

主要方法:

使用了人性化的,小鼠骨科和DEN/CCl4诱导的HCC模型.
使用ChIP测序,CUT&Tag和RNA测序来识别ETV5下游目标.
通过流细胞计和免疫光学分析了免疫细胞透和功能.
使用中和抗体研究了S100结合蛋白A9 (S100A9).

主要成果:

在HCC中ETV5过度表达促进了转移和免疫逃逸,通过招募多态核髓衍生的抑制细胞 (PMN-MDSCs).
ETV5上调调节了编程死亡干1 (PD-L1) 和S100A9,增强了PMN-MDSC免疫抑制.
抑制S100A9或准其受体 (TLR4/RAGE) 阻碍了ETV5诱导的PMN-MDSC招募.
此外,ETV5还在MDSC中提高了PD-L1的调节,增加了它们的免疫抑制功能.
骨髓细胞特异性Etv5淘汰赛减弱了HCC进展;中和S100A9抗体抑制了PMN-MDSC透.

结论:

通过增强PMN-MDSC的招募,透和激活,ETV5驱动HCC的进展和转移.
针对S100A9或TLR4/RAGE的联合疗法与抗PD-L1疗法显示出对ETV5阳性HCC治疗具有重大前景.

关键词:

癌症免疫生物学肝细胞癌细胞癌症免疫疗法免疫疗法

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