Kawaguchi Yoshihiko, Kono Koji, Mizukami Yoshiki, Mimura Kousaku, Fujii Hideki
First Department of Surgery, University of Yamanashi, Chuo-city, Yamanashi 409-3898, Japan.
Anticancer Res. 2009 Jun;29(6):2137-46.
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.
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.
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.
Lower susceptibility to the perforin-granzyme system is one of the important mechanisms explaining escape from trastuzumab-mediated ADCC.
导致曲妥珠单抗耐药的逃逸机制正在研究中，但尚无报告描述从曲妥珠单抗介导的抗体依赖性细胞毒性（ADCC）中逃逸的机制。在本研究中，使用食管鳞状细胞癌（SCC）细胞克隆阐明了从曲妥珠单抗介导的ADCC中逃逸的机制。
通过有限稀释法克隆对曲妥珠单抗介导的ADCC高度敏感的食管SCC细胞系TE4，得到对曲妥珠单抗介导的ADCC具有不同敏感性的SCC克隆。
肿瘤上人类表皮生长因子受体（HER）2的表达与对曲妥珠单抗介导的ADCC的敏感性之间无显著相关性。用γ干扰素处理或阻断自然杀伤（NK）细胞抑制性受体后，主要组织相容性复合体（MHC）I类表达的改变并未引起对曲妥珠单抗介导的ADCC敏感性的显著变化。然而，与对曲妥珠单抗介导的ADCC敏感性较高的肿瘤克隆相比，对曲妥珠单抗介导的ADCC敏感性较低的肿瘤克隆对穿孔素-颗粒酶系统的敏感性降低。
对穿孔素-颗粒酶系统的敏感性降低是解释从曲妥珠单抗介导的ADCC中逃逸的重要机制之一。
