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<p>Immune checkpoint therapy targeting PD-1/PD-L1 has shown promise in treating tumors, however, its clinical benefits are limited to a subset of gastric cancer (GC) patients. Recent research has highlighted a the correlation between PD-L1 expression and the clinical efficacy of anti-PD-1/PD-L1 therapies. Human cytomegalovirus (HCMV) has been implicated in GC, but its specific role in modulating this disease remains elusive. In this study, we analyzed clinical tissue samples using bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR). We found that GC tissues infected with HCMV presented higher PD-L1 expression compared to those without virus. Furthermore, we demonstrated that HCMV infection enhances PD-L1 expression in GC cells. Cytotoxicity assays revealed that HCMV modulates cancer immune responses via the PD-1/PD-L1 pathway. Mechanistically, we showed that HCMV activates the PI3K-Akt signaling cascade and modulates PD-L1 expression through its tegument protein UL23. Functionally, increased UL23 expression leads to elevated PD-L1 levels, which diminishes tumor cell sensitivity to T-cell-mediated cytotoxicity and triggers T-cell apoptosis. Additionally, in vivo experiments revealed that UL23-induced PD-L1 upregulation inhibits CD8<sup>+</sup> T-cell infiltration and reduces the expression of inflammatory factors in tumor microenvironment, ultimately weakening antitumor immunity. Our findings reveal a novel mechanism whereby HCMV and its tegument protein UL23 contribute to cancer immunosuppression through the regulation of PD-L1 expression. This discovery may serve as a potential therapeutic target for enhancing the efficacy of cancer immunotherapy.</p>

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Human cytomegalovirus tegument protein UL23 promotes gastric cancer immune evasion by facilitating PD-L1 transcription

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月11日

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  • Shiyu Feng,
  • Yitian Shen,
  • Haoke Zhang,
  • Wanfeng Liu,
  • Weixu Feng,
  • Xiuting Chen,
  • Liang Zhang,
  • Jiangli Chen,
  • Mingdong Lu,
  • Xiangyang Xue,
  • Xian Shen

摘要

Immune checkpoint therapy targeting PD-1/PD-L1 has shown promise in treating tumors, however, its clinical benefits are limited to a subset of gastric cancer (GC) patients. Recent research has highlighted a the correlation between PD-L1 expression and the clinical efficacy of anti-PD-1/PD-L1 therapies. Human cytomegalovirus (HCMV) has been implicated in GC, but its specific role in modulating this disease remains elusive. In this study, we analyzed clinical tissue samples using bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR). We found that GC tissues infected with HCMV presented higher PD-L1 expression compared to those without virus. Furthermore, we demonstrated that HCMV infection enhances PD-L1 expression in GC cells. Cytotoxicity assays revealed that HCMV modulates cancer immune responses via the PD-1/PD-L1 pathway. Mechanistically, we showed that HCMV activates the PI3K-Akt signaling cascade and modulates PD-L1 expression through its tegument protein UL23. Functionally, increased UL23 expression leads to elevated PD-L1 levels, which diminishes tumor cell sensitivity to T-cell-mediated cytotoxicity and triggers T-cell apoptosis. Additionally, in vivo experiments revealed that UL23-induced PD-L1 upregulation inhibits CD8+ T-cell infiltration and reduces the expression of inflammatory factors in tumor microenvironment, ultimately weakening antitumor immunity. Our findings reveal a novel mechanism whereby HCMV and its tegument protein UL23 contribute to cancer immunosuppression through the regulation of PD-L1 expression. This discovery may serve as a potential therapeutic target for enhancing the efficacy of cancer immunotherapy.