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, Shuqun Cheng, Jianjun Luo, Runsheng Chen, Pengyuan Yang
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. Here authors show that EVs derived from hepatocellular carcinomas may contain the long noncoding RNA, HDAC2-AS2, which suppresses antitumour CD8 + T cells by interfering with transcriptional and epigenetic regulation of their activated, cytotoxic functional state.