Mechanisms of escape from trastuzumab-mediated ADCC in esophageal squamous cell carcinoma: relation to susceptibility to perforin-granzyme

Anticancer Res. 2009 Jun;29(6):2137-46.

Abstract

Background: The escape mechanisms leading to trastuzumab-resistance are under investigation, but no report has yet described the mechanisms of escape from trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). In the present study, the mechanisms of escape from trastuzumab-mediated ADCC were elucidated using esophageal squamous cell carcinoma (SCC) cell clones.

Materials and methods: The esophageal SCC cell line TE4, which is highly susceptible to trastuzumab-mediated ADCC, was cloned by limited dilution, resulting in SCC clones with different sensitivities to trastuzumab-mediated ADCC.

Results: There was no significant correlation between human epidermal growth factor receptor (HER) 2-expression on the tumor and the sensitivity to trastuzumab-mediated ADCC. Altered major histocompatibility complex (MHC) class I expression treated by IFN-gamma or the blocking of natural killer (NK) cell inhibitory receptors did not induce significant changes in sensitivity to trastuzumab-mediated ADCC. However, the tumor clones with a lower sensitivity to trastuzumab-mediated ADCC showed a reduced susceptibility to the perforin-granzyme system compared to those with a greater sensitivity to trastuzumab-mediated ADCC.

Conclusion: Lower susceptibility to the perforin-granzyme system is one of the important mechanisms explaining escape from trastuzumab-mediated ADCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antibody-Dependent Cell Cytotoxicity*
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Esophageal Neoplasms / drug therapy
  • Esophageal Neoplasms / immunology*
  • Esophageal Neoplasms / pathology
  • Flow Cytometry
  • Granzymes / metabolism*
  • Humans
  • Killer Cells, Natural / immunology
  • Perforin / metabolism*
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / metabolism
  • Trastuzumab

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Perforin
  • Receptor, ErbB-2
  • Granzymes
  • Trastuzumab