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Background <p>To address the limited immunogenicity and immune evasion in hepatocellular carcinoma (HCC), this study developed a combinatorial immunotherapy strategy combining antigen-specific vaccination, epigenetic modulation, and TIGIT-targeted checkpoint blockade.</p> Methods <p>Bioinformatic screening identified the cancer-testis antigen MAEL as a target. HLA-A*02:01-restricted MAEL peptides were used to pulse monocyte-derived dendritic cells (DCs), which primed cytotoxic T lymphocytes (CTLs). The CTL cytotoxicity against HCC cells was tested. HCC cells were treated with the HDAC inhibitor vorinostat to enhance MAEL expression, and its impact on CTL killing was evaluated. The triple combination (MAEL specific CTLs + vorinostat + anti-TIGIT) was tested in HCC&#xa0;xenograft mouse models, with analyses of tumor growth, survival, and immune infiltration.</p> Results <p>MAEL was confirmed as an HCC-associated antigen with restricted normal tissue expression. MAEL peptide-pulsed DCs generated potent CTLs with cytotoxicity against HLA-A*02:01⁺ HCC lines. Vorinostat upregulated MAEL expression, enhancing CTL killing (<i>p</i> &lt; 0.01). In vivo, the dual combination (MAEL specific CTLs + vorinostat) outperformed monotherapies, reducing tumor growth and prolonging survival. The triple combination achieved the strongest anti-tumor effects, with significant regression and extended survival, via increased activated MAEL specific CD8⁺ T cell infiltration and enhanced CTL effector functions (elevated IFN-<i>γ</i>, TNF-<i>α</i>).</p> Conclusion <p>This triple combination strategy synergistically enhances HCC immunotherapy. Vorinostat induces MAEL expression to “unmask” tumors, while TIGIT blockade overcomes T cell exhaustion, amplifying antigen-specific CTL activity. This approach shows promise for HCC treatment.</p>

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Vorinostat unmasks MAEL to enhance DC vaccine-induced CTL killing in hepatocellular carcinoma, potentiated by TIGIT checkpoint inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Can Liu,
  • Qianru Zhang,
  • Jingjing Zhang,
  • Wenpeng Liu,
  • Shengya Geng,
  • Jiandong Zhang

摘要

Background

To address the limited immunogenicity and immune evasion in hepatocellular carcinoma (HCC), this study developed a combinatorial immunotherapy strategy combining antigen-specific vaccination, epigenetic modulation, and TIGIT-targeted checkpoint blockade.

Methods

Bioinformatic screening identified the cancer-testis antigen MAEL as a target. HLA-A*02:01-restricted MAEL peptides were used to pulse monocyte-derived dendritic cells (DCs), which primed cytotoxic T lymphocytes (CTLs). The CTL cytotoxicity against HCC cells was tested. HCC cells were treated with the HDAC inhibitor vorinostat to enhance MAEL expression, and its impact on CTL killing was evaluated. The triple combination (MAEL specific CTLs + vorinostat + anti-TIGIT) was tested in HCC xenograft mouse models, with analyses of tumor growth, survival, and immune infiltration.

Results

MAEL was confirmed as an HCC-associated antigen with restricted normal tissue expression. MAEL peptide-pulsed DCs generated potent CTLs with cytotoxicity against HLA-A*02:01⁺ HCC lines. Vorinostat upregulated MAEL expression, enhancing CTL killing (p < 0.01). In vivo, the dual combination (MAEL specific CTLs + vorinostat) outperformed monotherapies, reducing tumor growth and prolonging survival. The triple combination achieved the strongest anti-tumor effects, with significant regression and extended survival, via increased activated MAEL specific CD8⁺ T cell infiltration and enhanced CTL effector functions (elevated IFN-γ, TNF-α).

Conclusion

This triple combination strategy synergistically enhances HCC immunotherapy. Vorinostat induces MAEL expression to “unmask” tumors, while TIGIT blockade overcomes T cell exhaustion, amplifying antigen-specific CTL activity. This approach shows promise for HCC treatment.