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<p>Epstein–Barr virus (EBV) infection accounts for approximately 10% of gastric cancer (GC) cases and is strongly linked to immune evasion, although the precise mechanisms remain unclear. Transporter associated with antigen processing 1 (TAP1), a member of ATP-binding cassette subfamily B, is overexpressed in EBV-associated gastric cancer (EBVaGC) and is implicated in tumor immune evasion. TAP1 expression levels in EBV-positive and EBV-negative gastric cancer samples were analyzed using TCGA and GEO datasets. Molecular biology techniques were used to investigate the regulatory pathways involved in TAP1. The role of TAP1 in modulating immunotherapy responses was validated using T-cell cytotoxicity assays and mouse models. TAP1 was significantly overexpressed in EBV-positive gastric cancer tissues and cell lines. Mechanistic studies revealed that EBV latent membrane protein 2A (LMP2A) activates the NF-κB P65 pathway, which directly binds to the TAP1 promoter and enhances transcription. Furthermore, TAP1 expression was positively correlated with PD-L1 levels. In immunocompetent mice, shTAP1 MFC cells exhibited significantly reduced growth relative to that in immunodeficient mice. TAP1 upregulates PD-L1 via the JNK/STAT1 pathway, thereby influencing tumor immunotherapy responses. Notably, TAP1 silencing combined with PD-1 monoclonal antibody treatment significantly inhibited gastric cancer cell proliferation. This study revealed a mechanism through which the EBV protein LMP2A drives TAP1 expression via NF-κB signaling. TAP1, in turn, regulates PD-L1 expression via the JNK/STAT1 pathway, contributing to immune evasion. These findings highlight TAP1 as a promising therapeutic target for improving the efficacy of immunotherapy in gastric cancer.</p>

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TAP1 promotes immune escape by activating JNK/STAT1/PD-L1 signaling in EBV-associated gastric cancer

  • 期刊论文

  • 发表日期：

    2025年6月11日

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  • Wenqing Shan,
  • Guoqingyuan Li,
  • Hailing Zhang,
  • Ranran Zhang,
  • Jialong Liu,
  • Liping Gao,
  • Yizhang Li,
  • Lilan Fan,
  • Chaoran Yang,
  • Jing Liu

摘要

Epstein–Barr virus (EBV) infection accounts for approximately 10% of gastric cancer (GC) cases and is strongly linked to immune evasion, although the precise mechanisms remain unclear. Transporter associated with antigen processing 1 (TAP1), a member of ATP-binding cassette subfamily B, is overexpressed in EBV-associated gastric cancer (EBVaGC) and is implicated in tumor immune evasion. TAP1 expression levels in EBV-positive and EBV-negative gastric cancer samples were analyzed using TCGA and GEO datasets. Molecular biology techniques were used to investigate the regulatory pathways involved in TAP1. The role of TAP1 in modulating immunotherapy responses was validated using T-cell cytotoxicity assays and mouse models. TAP1 was significantly overexpressed in EBV-positive gastric cancer tissues and cell lines. Mechanistic studies revealed that EBV latent membrane protein 2A (LMP2A) activates the NF-κB P65 pathway, which directly binds to the TAP1 promoter and enhances transcription. Furthermore, TAP1 expression was positively correlated with PD-L1 levels. In immunocompetent mice, shTAP1 MFC cells exhibited significantly reduced growth relative to that in immunodeficient mice. TAP1 upregulates PD-L1 via the JNK/STAT1 pathway, thereby influencing tumor immunotherapy responses. Notably, TAP1 silencing combined with PD-1 monoclonal antibody treatment significantly inhibited gastric cancer cell proliferation. This study revealed a mechanism through which the EBV protein LMP2A drives TAP1 expression via NF-κB signaling. TAP1, in turn, regulates PD-L1 expression via the JNK/STAT1 pathway, contributing to immune evasion. These findings highlight TAP1 as a promising therapeutic target for improving the efficacy of immunotherapy in gastric cancer.