癌症研究
癌变
免疫系统
免疫检查点
免疫疗法
癌症免疫疗法
生物
CD8型
肝细胞癌
肝癌
癌症
免疫学
遗传学
作者
Zhao‐Ru Dong,Jia‐Bin Cai,Guohai Shi,Yafei Yang,Xiaoyong Huang,Chi Zhang,Rui‐Zhao Dong,Chuan‐Yuan Wei,Tao Li,Aiwu Ke,Jian‐Gao Fan
出处
期刊:Cancer Letters
[Elsevier]
日期:2023-06-01
卷期号:564: 216186-216186
被引量:6
标识
DOI:10.1016/j.canlet.2023.216186
摘要
Evading immune destruction is an emerging hallmark of cancer and a potential key step in tumorigenesis. Immune checkpoint blocker (ICB)-based combination therapies revolutionize the landscape of systemic therapy for HCC. However, the molecular underpinnings governing immune evasion and responses remain unclear. Our study aims to find new regulatory molecules that drive HCC immune escape and tumorigenesis and find new promising immunotherapeutic approaches for HCC. In our study, laser capture microdissection (LCM) and miRNA sequencing combined with in vitro and in vivo experiments identified miR-93-5p as a crucial initiating oncogene during liver progenitor cell (LPC) malignant transformation and immune escape. Mechanistically, miR-93-5p could directly target canonical tumour suppressors such as APC to promote LPC malignant transformation and hepatocarcinogenesis. More importantly, miR-93-5p could induce deviant GAL-9 augmentation to inactivate infiltrated CD8(+) T cells and induce immune evasion by targeting several epigenetic regulators, such as AEBP2, and then regulating H3K4me3/H3K27me3 bivalency. Experiments in C57BL/6 mice demonstrated that blockade of Gal-9 abrogated miR-93-5p-induced HCC progression and improved their prognosis. Clinically, we identified a unique subtype of HCC closely associated with high GAL-9 expression and anti-PD1 treatment resistance. Our study highlights the pivotal role of the miR-93-5p/Gal-9 axis in driving HCC immune escape and tumorigenesis. Blocking GAL-9 is an effective and promising immunotherapeutic approach for HCC.
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