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

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.