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.

Abstract

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 (PBMCs(KLRG1(-))).

• Authors: Chisako Yamauchi, Satoshi Fujii, Taichi Kimura, Takeshi Kuwata, Noriaki Wada, Hirofumi Mukai, Naoki Matsumoto, Masashi Fukayama, Atsushi Ochiai
• Journal: International journal of cancer (Int J Cancer) Vol. 128 Issue 9 Pg. 2125-37 (May 01 2011) ISSN: 1097-0215 [Electronic] United States
• PMID: 21387286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Cadherins
• KLRG1 protein, human
• Lectins, C-Type
• Receptors, Immunologic
• Trans-Activators
• Receptor, ErbB-2
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, genetics, immunology)
• Cadherins (biosynthesis)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (immunology)
• Female
• Humans
• Immunohistochemistry
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Lectins, C-Type (immunology, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Receptor, ErbB-2 (genetics)
• Receptors, Immunologic
• Trans-Activators (immunology, metabolism)
• Trastuzumab
• Xenograft Model Antitumor Assays