E‐cadherin expression on human carcinoma cell affects trastuzumab‐mediated antibody‐dependent cellular cytotoxicity through killer cell lectin‐like receptor G1 on natural killer cells

• Published in: International journal of cancer 2011-05, Vol.128 (9), p.2125-2137
• Main Authors: Yamauchi, Chisako, Fujii, Satoshi, Kimura, Taichi, Kuwata, Takeshi, Wada, Noriaki, Mukai, Hirofumi, Matsumoto, Naoki, Fukayama, Masashi, Ochiai, Atsushi
• Format: Article
• Language: English
• Subjects: ADCC; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity - immunology; Antibody-dependent cell-mediated cytotoxicity; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Breast carcinoma; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Cadherins - biosynthesis; Cell Line, Tumor; Cytotoxicity; Drug Resistance, Neoplasm - immunology; E-Cadherin; Female; HER2; Humans; Immune response; Immunohistochemistry; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; KLRG1; KLRG1 protein; Lectins, C-Type - immunology; Lectins, C-Type - metabolism; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Natural killer cells; Peripheral blood mononuclear cells; Receptor mechanisms; Receptor, ErbB-2 - genetics; Trans-Activators - immunology; Trans-Activators - metabolism; Trastuzumab; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.25803

Trastuzumab is a recombinant antibody drug that is widely used for the treatment of HER2‐overexpressing breast carcinoma. Despite encouraging clinical results, many HER2‐overexpressing carcinomas are primarily resistant to trastuzumab. We attempted to explain trastuzumab resistance and search for solutions. Since the killer cell lectin‐like receptor G1 (KLRG1), an inhibitory receptor expressed on subsets of natural killer (NK) cells recognizes E‐cadherin as ligands and may inhibit immune responses by regulating the effector function of NK cells, we used HER2‐overexpressing carcinoma cells which were expressing E‐cadherin to investigate the role of antibody‐dependent cellular cytotoxicity (ADCC) through KLRG1 on NK cells in vitro and vivo. The results indicated that HER2‐overexpressing carcinoma cells were killed by trastuzumab‐mediated ADCC and the ADCC activity was reflected the degree of E‐cadherin expression on carcinoma cells. We found that expression of E‐cadherin was shown to be a predictor of response to trastuzumab‐based treatment for HER2‐overexpressing carcinomas, furthermore, trastuzumab‐mediated ADCC was markedly enhanced by KLRG1‐negative peripheral blood mononuclear cells (PBMCsKLRG1(−)).