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.


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.


CONCLUSIONS
Lower susceptibility to the perforin-granzyme system is one of the important mechanisms explaining escape from trastuzumab-mediated ADCC.
Kawaguchi
Yoshihiko
Y
First Department of Surgery, University of Yamanashi, Chuo-city, Yamanashi 409-3898, Japan.
Kono
Koji
K
Mizukami
Yoshiki
Y
Mimura
Kousaku
K
Fujii
Hideki
H
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D054353:Perforin / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D053804:Granzymes; D054353:Perforin; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab