Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines
Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines
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DOI：
10.1158/1078-0432.ccr-06-1726
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发表时间：
2007-03-01
影响因子：
11.5
通讯作者：
Shimizu, Eiji
中科院分区：
文献类型：
--
作者：
Kurai, Jun;Chikumi, Hiroki;Shimizu, Eiji
目的：表皮生长因子受体（EGFR）在肺癌中普遍过表达。西妥昔单抗是一种靶向EGFR的小鼠-人嵌合抗体。与其抑制作用相比，其免疫机制尚未得到很好的研究。在这项研究中，我们研究了西妥昔单抗对肺癌细胞系的抗体依赖性细胞毒性（ADCC）活性。实验设计：研究肺癌细胞系EGFR表达与西妥昔单抗ADCC活性的相关性，以及白细胞介素-2和化疗对ADCC活性的影响。通过定量流式细胞分析和免疫组织化学检测EGFR的表达。采用4 h Cr-51释放法测定ADCC活性。外周血单核细胞、纯化的T细胞、自然杀伤（NK）细胞和来自健康供体或肺癌患者的单核细胞被用作效应细胞。结果：新鲜外周血单核细胞在低浓度西妥昔单抗（0.25 μ g/mL）下表现出西妥昔单抗介导的抗肺癌细胞系ADCC活性。egfr数量与ADCC活性呈对数相关。即使EGFR表达较低（免疫组织化学检测不到），也足以使ADCC活性最大化，靶细胞上EGFR表达的进一步增加对ADCC活性没有进一步的影响。此外，白细胞介素-2主要通过激活NK细胞增强ADCC活性，并且在肺癌患者中，ADCC对化疗免疫抑制的敏感性低于NK细胞活性。结论：这些观察结果提示ADCC活性作为西妥昔单抗在肺癌患者生物治疗中的免疫机制的重要性。
Purpose: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines.Experimental Design: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h Cr-51 release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells.Results: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 mu g/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients.Conclusions: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.