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Author Spotlight: Optimizing Antibody-Based Cancer Treatments via Antibody-Dependent, Cell-Mediated Cytotoxicity Assay
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T-cell activation enhances anti-HER2-mediated antibody-dependent cellular cytotoxicity in gastric cancer

Zirui Xue1,2, Zhaoming Wang1,2, Dan Liu1,2

  • 1Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Immunologic Research
|June 2, 2025
PubMed

Insights

Lack of T cell help is a novel resistance mechanism to anti-HER2 monoclonal antibody (mAb) therapy in HER2-positive gastric cancer. Activating T cells with a bispecific antibody (bsAb) enhances anti-tumor effects and improves patient outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Gastroenterology

Background:

  • Anti-HER2 monoclonal antibody (mAb) therapy is standard for advanced HER2-positive gastric cancer.
  • Therapeutic resistance to anti-HER2 mAb remains a significant clinical challenge.

Purpose of the Study:

  • To identify novel resistance mechanisms to anti-HER2 mAb in gastric cancer.
  • To investigate the role of intratumoral immune cells in anti-HER2 therapy response.
  • To propose strategies for enhancing anti-HER2 mAb efficacy by modulating T cell responses.

Main Methods:

  • Co-culture of peripheral blood mononuclear cells (PBMCs) with HER2-positive gastric cancer cells/organoids to assess NK cell responses to anti-HER2 mAb.
  • T cell depletion or activation assays to evaluate their impact on antibody-dependent cellular cytotoxicity (ADCC).
  • Evaluation of combinatorial therapy using anti-HER2 mAb and HER2×CD3 T cell-engaging bispecific antibody (bsAb) in preclinical models and patient samples.

Main Results:

  • Higher intratumoral T cell infiltration correlated with greater tumor regression and improved overall survival in patients receiving anti-HER2 mAb.
  • T cells, particularly CD4+ T cells, influence NK cell function via IL-2 production, impacting ADCC.
  • Combination therapy with HER2×CD3 bsAb enhanced anti-tumor activity of anti-HER2 mAb by activating T cells.

Conclusions:

  • Lack of T cell help represents a novel resistance mechanism to anti-HER2 mAb in gastric cancer.
  • Enhancing T cell activation through HER2×CD3 bsAb can overcome resistance and improve therapeutic efficacy of anti-HER2 mAb.
  • Targeting T cell-mediated immunity offers a promising strategy to enhance anti-HER2 therapy for gastric cancer patients.
Keywords:
ADCCAnti-HER2Bispecific antibodyNK cell

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