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<p>Anti-HER2 monoclonal antibody (mAb) is the standard first-line therapy for advanced HER2<sup>+</sup> gastric cancer. However, resistance to anti-HER2 therapy remains a significant clinical challenge. In this study, we identified a novel resistance mechanism to anti-HER2 therapy in gastric cancer and proposed a strategy to enhance therapeutic efficacy by activating T cells. The association between intratumoral immune cells and clinical responses to anti-HER2 therapy in gastric cancer was investigated. Peripheral blood mononuclear cells (PBMCs) were co-cultured with HER2<sup>+</sup> gastric cancer cell lines or organoids to study NK cell responses mediated by anti-HER2 mAb. T cells were depleted or activated to assess their impact on antibody-dependent cellular cytotoxicity (ADCC), and the mechanism by which T cells influence ADCC was examined. The combinatorial effects of anti-HER2 mAb and HER2 × CD3 T cell-engaging bispecific antibody (bsAb) in gastric cancer were evaluated. A total of 35 gastric cancer patients receiving anti-HER2 mAb treatment were enrolled. A higher number of intratumoral T cells were associated with greater tumor regression and improved overall survival following anti-HER2 mAb therapy. Mechanistically, T cells, mainly CD4<sup>+</sup> T cells, influence NK cell functional and phenotypic changes via interleukin-2 (IL-2) production. Activating T cells by HER2 × CD3 T cell-engaging bsAb enhanced the anti-tumor effects of anti-HER2 mAb in gastric cancer. Our study identified the lack of T cell help as a novel resistance mechanism to anti-HER2 mAb in gastric cancer. Enhancing T cell help via the combination of HER2 × CD3 bsAb improved the therapeutic efficacy of anti-HER2 mAb in gastric cancer.</p>

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T-cell activation enhances anti-HER2-mediated antibody-dependent cellular cytotoxicity in gastric cancer

  • 期刊论文

  • 发表日期：

    2025年6月2日

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  • Zirui Xue,
  • Zhaoming Wang,
  • Dan Liu,
  • Bosen Li,
  • Zhaodong Sun,
  • Junjie Zhao,
  • Haojie Li,
  • Xuefei Wang,
  • Yihong Sun

摘要

Anti-HER2 monoclonal antibody (mAb) is the standard first-line therapy for advanced HER2+ gastric cancer. However, resistance to anti-HER2 therapy remains a significant clinical challenge. In this study, we identified a novel resistance mechanism to anti-HER2 therapy in gastric cancer and proposed a strategy to enhance therapeutic efficacy by activating T cells. The association between intratumoral immune cells and clinical responses to anti-HER2 therapy in gastric cancer was investigated. Peripheral blood mononuclear cells (PBMCs) were co-cultured with HER2+ gastric cancer cell lines or organoids to study NK cell responses mediated by anti-HER2 mAb. T cells were depleted or activated to assess their impact on antibody-dependent cellular cytotoxicity (ADCC), and the mechanism by which T cells influence ADCC was examined. The combinatorial effects of anti-HER2 mAb and HER2 × CD3 T cell-engaging bispecific antibody (bsAb) in gastric cancer were evaluated. A total of 35 gastric cancer patients receiving anti-HER2 mAb treatment were enrolled. A higher number of intratumoral T cells were associated with greater tumor regression and improved overall survival following anti-HER2 mAb therapy. Mechanistically, T cells, mainly CD4+ T cells, influence NK cell functional and phenotypic changes via interleukin-2 (IL-2) production. Activating T cells by HER2 × CD3 T cell-engaging bsAb enhanced the anti-tumor effects of anti-HER2 mAb in gastric cancer. Our study identified the lack of T cell help as a novel resistance mechanism to anti-HER2 mAb in gastric cancer. Enhancing T cell help via the combination of HER2 × CD3 bsAb improved the therapeutic efficacy of anti-HER2 mAb in gastric cancer.