2. Academic Validation
  3. Overcoming NK cell resistance in triple-negative breast cancer via adcc with a humanized anti-CD147 antibody

Overcoming NK cell resistance in triple-negative breast cancer via adcc with a humanized anti-CD147 antibody

  • Cancer Immunol Immunother. 2025 Oct 22;74(11):342. doi: 10.1007/s00262-025-04203-z.
Thanathat Pamonsupornwichit 1,  Kanyarat Thongheang 1 2,  Nuchjira Takheaw 2 3,  Kanokporn Sornsuwan 1 4,  Zaw Ye Htet 1,  On-Anong Juntit 1 4,  Phatcharida Jantaree 5,  Chatchai Tayapiwatana 6 7
Affiliations

Affiliations

  • 1 Center of Biomolecular Therapy and Diagnostic, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
  • 2 Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
  • 3 Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
  • 4 Office of Research Administration, Chiang Mai University, Chiang Mai, 50200, Thailand.
  • 5 Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. phatcharida.j@cmu.ac.th.
  • 6 Center of Biomolecular Therapy and Diagnostic, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand. chatchai.t@cmu.ac.th.
  • 7 Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand. chatchai.t@cmu.ac.th.
PMID: 41123660 DOI: 10.1007/s00262-025-04203-z
Abstract

Triple-negative breast Cancer (TNBC) is an aggressive and clinically challenging subtype defined by the absence of Estrogen receptor, Progesterone Receptor, and HER2 amplification, resulting in poor prognosis and limited therapeutic options. Targeting alternative molecular pathways is urgently needed to overcome resistance and improve patient outcomes. CD147 has emerged as surface marker associated with tumor progression and immune evasion. In this study, CD147 and MHC class I-a key inhibitory ligand for natural killer cells-were analyzed in breast Cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and HCC38) using flow cytometry. The therapeutic efficacy of a humanized anti-CD147 monoclonal antibody (HuM6-1B9) was evaluated for its capacity to potentiate antibody-dependent cellular cytotoxicity (ADCC). HuM6-1B9 demonstrated the strong binding to MDA-MB-231 (KD = 4.982 nM) and HCC38 (KD = 4.523 nM), which are representative TNBC cell lines. In 3D spheroid models, HuM6-1B9 significantly enhanced PBMC-mediated ADCC, leading to a marked reduction in TNBC spheroid viability. Co-culture of CFSE-labeled MDA-MB-231 and HCC38 cells with primary NK cells confirmed robust ADCC, achieving 50% and 70% cytotoxicity, respectively, despite high MHC class I expression. Live-cell imaging demonstrated Caspase-3/7 activation consistent with Apoptosis in NK-targeted tumor cells, while CD107a degranulation and IFN-γ secretion confirmed the functional contribution of HuM6-1B9 to ADCC enhancement. Importantly, HuM6-1B9 did not promote migration or invasion in MDA-MB-231 cells, supporting its safety profile regarding metastasis. Collectively, these findings establish HuM6-1B9 as a promising immunotherapeutic candidate that overcomes immune resistance and selectively eliminates TNBC cells through ADCC without enhancing metastatic potential. By integrating mechanistic assays of NK cytotoxicity, Apoptosis, and 3D tumor spheroids, this study provides clinically relevant insights underscoring the translational potential of HuM6-1B9 in TNBC immunotherapy.

Keywords

ADCC; Breast cancer; CD147; Humanized antibody; Immunotherapy; NK cell; TNBC.

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