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<p>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 <i>HDAC2-AS2</i>. EVs enriched with <i>HDAC2-AS2</i> facilitate cancer progression by suppressing cytotoxicity of intra-tumor CD8<sup>+</sup> T cells. Mechanistically, in activated cytotoxic CD8<sup>+</sup> T cells, translocation of the transcription factor cyclin-dependent kinase 9 (CDK9), to the cytoplasm is critical for functional integrity. <i>HDAC2-AS2</i> targets and blocks cytosolic CDK9, and this results in exhaustion of PD-1<sup>+</sup>CD8<sup>+</sup> T cells and suppression of IFN-γ<sup>+</sup>CD8<sup>+</sup> T cell cytotoxicity. Notably, we demonstrate that low <i>CDK9</i> and high <i>HDAC2-AS2</i> 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<sup>+</sup> T cell immunity to promote tumorigenesis, and highlight extracellular <i>HDAC2-AS2</i> as a promising biomarker and therapeutic target for HCC.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月28日

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  • 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

摘要

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.