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HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2

Author

Listed:
  • Yanan Gao

    (Chinese Academy of Sciences)

  • Zhenxing Zhang

    (Chinese Academy of Sciences)

  • Xuetao Huang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Maojun You

    (Chinese Academy of Sciences)

  • Chengzhi Du

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Nan Li

    (Naval Medical University)

  • Yajing Hao

    (Chinese Academy of Sciences)

  • Kang Wang

    (Naval Medical University)

  • Xiang Ding

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Fuquan Yang

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Shu-qun Cheng

    (Naval Medical University)

  • Jianjun Luo

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Runsheng Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Pengyuan Yang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • 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, 2025. "HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57367-8
    DOI: 10.1038/s41467-025-57367-8
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    References listed on IDEAS

    as
    1. Yiming Lu & Aiqing Yang & Cheng Quan & Yingwei Pan & Haoyun Zhang & Yuanfeng Li & Chengming Gao & Hao Lu & Xueting Wang & Pengbo Cao & Hongxia Chen & Shichun Lu & Gangqiao Zhou, 2022. "A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Runqiu Jiang & Junwei Tang & Yun Chen & Lei Deng & Jie Ji & Yu Xie & Ke Wang & Wei Jia & Wen-Ming Chu & Beicheng Sun, 2017. "The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
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