Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Int J Cancer. 2011 May 1;128(9):2125-37. 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 (PBMCs(KLRG1(-))).
曲妥珠单抗是一种重组抗体药物，广泛用于治疗 HER2 过表达型乳腺癌。尽管临床结果令人鼓舞，但许多 HER2 过表达型乳腺癌主要对曲妥珠单抗耐药。我们试图解释曲妥珠单抗耐药性并寻找解决方案。由于杀伤细胞凝集素样受体 G1（KLRG1）是一种表达在自然杀伤（NK）细胞亚群上的抑制性受体，其识别 E-钙黏蛋白作为配体，并可能通过调节 NK 细胞的效应功能来抑制免疫反应，因此我们使用表达 E-钙黏蛋白的 HER2 过表达型癌细胞来研究通过 NK 细胞上的 KLRG1 进行抗体依赖性细胞毒性（ADCC）在体外和体内对 HER2 过表达型乳腺癌的作用。结果表明，HER2 过表达型癌细胞被曲妥珠单抗介导的 ADCC 杀死，ADCC 活性反映了癌细胞上 E-钙黏蛋白表达的程度。我们发现，E-钙黏蛋白的表达被证明是预测曲妥珠单抗治疗 HER2 过表达型乳腺癌反应的一个指标，此外，KLRG1 阴性外周血单核细胞（PBMCs（KLRG1（-）））显著增强了曲妥珠单抗介导的 ADCC。
