2025-03-05 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202503/t20250310_903492.shtml
- https://www.nature.com/articles/s41467-025-57367-8
HBV関連肝細胞がんはロングノンコーディングRNA HDAC2-AS2を介して抗腫瘍CD8+ T細胞を阻害する HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2
Yanan Gao,Zhenxing Zhang,Xuetao Huang,Maojun You,Chengzhi Du,Nan Li,Yajing Hao,Kang Wang,Xiang Ding,Fuquan Yang,Shu-qun Cheng,Jianjun Luo,Runsheng Chen &Pengyuan Yang
Nature Communications Published:28 February 2025
DOI:https://doi.org/10.1038/s41467-025-57367-8
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Extracellular vesicles (EV) are critical mediators of intercellular communication within the tumor microenvironment, and cancer-cell-secreted EVs often facilitate cancer progression. Here we show that in HBV-associated HCC, tumor-cell-derived EVs contain a TGFβ-inducible long noncoding RNA, termed HDAC2-AS2. EVs enriched with HDAC2-AS2 facilitate cancer progression by suppressing cytotoxicity of intra-tumor CD8+ T cells. Mechanistically, in activated cytotoxic CD8+ T cells, translocation of the transcription factor cyclin-dependent kinase 9 (CDK9), to the cytoplasm is critical for functional integrity. HDAC2-AS2 targets and blocks cytosolic CDK9, and this results in exhaustion of PD-1+CD8+ T cells and suppression of IFN-γ+CD8+ T cell cytotoxicity. Notably, we demonstrate that low CDK9 and high HDAC2-AS2 expressions are associated with poor survival of HCC, which can be rescued by anti-PD-1 therapy. These findings emphasize the significance of tumor-derived EVs in suppressing antitumor CD8+ T cell immunity to promote tumorigenesis, and highlight extracellular HDAC2-AS2 as a promising biomarker and therapeutic target for HCC.
