Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55131, Mainz, Germany.
Int J Cancer. 2015 Feb 15;136(4):821-30. doi: 10.1002/ijc.29037. Epub 2014 Jun 26.
Anti-EGFR monoclonal antibodies (mAb) like Cetuximab are commonly used for treatment of EGFR+ solid tumors mainly by exerting their therapeutic effect through inhibition of signal transduction. Additionally, IgG1 is a potent mediator of antibody-dependent cytotoxicity (ADCC). In case of the IgG1, Cetuximab induction of ADCC in vivo is controversially discussed. In our study, we investigated the efficiency of Cetuximab-mediated ADCC in a humanized mouse tumor model in vivo and analyzed the contribution of immunologic processes toward antitumor activity. Therefore, we used immunodeficient NOD/Scid mice transgenic for human MHC class I molecule HLA-A2 and adoptively transferred human HLA-A2+ PBMC after engraftment of human epidermoid cell carcinoma A431. Here, we show that high doses of anti-EGFR mAb induced strong tumor regression independent of the immune system. However, tumor regression by low doses of anti-EGFR mAb treatment was ADCC dependent and mediated by tumor infiltrating CD8+ T effector cells. This novel mechanism of ADCC conducted by CD8+ T effector cells was restricted to IgG1 anti-EGFR mAb, dependent of binding to CD16 on T cells and could be inhibited after EGFR blockade on tumor cells. Furthermore, CD8+ T effector cell-mediated ADCC was enhanced in the presence of IL-15 and strongly improved after glycosylation of anti-EGFR mAb indicating the potential of glycoengineered therapeutic mAb as efficient biologicals in cancer therapy.
抗 EGFR 单克隆抗体（mAb），如西妥昔单抗，常用于治疗 EGFR+实体瘤，主要通过抑制信号转导发挥治疗作用。此外，IgG1 是抗体依赖的细胞毒性（ADCC）的有效介质。在 IgG1 的情况下，西妥昔单抗在体内诱导 ADCC 存在争议。在我们的研究中，我们在体内人源化小鼠肿瘤模型中研究了西妥昔单抗介导的 ADCC 的效率，并分析了免疫过程对肿瘤活性的贡献。因此，我们使用免疫缺陷 NOD/Scid 小鼠，其转染了人 MHC Ⅰ类分子 HLA-A2，并在移植人表皮癌细胞 A431 后过继转移人 HLA-A2+PBMC。在这里，我们表明高剂量的抗 EGFR mAb 诱导强烈的肿瘤消退，而与免疫系统无关。然而，低剂量的抗 EGFR mAb 治疗诱导的肿瘤消退依赖于 ADCC，并且由肿瘤浸润的 CD8+T 效应细胞介导。这种由 CD8+T 效应细胞介导的 ADCC 的新机制仅限于 IgG1 抗 EGFR mAb，依赖于 T 细胞上 CD16 的结合，并且可以在肿瘤细胞上的 EGFR 阻断后被抑制。此外，在存在 IL-15 的情况下，CD8+T 效应细胞介导的 ADCC 增强，并且在抗 EGFR mAb 糖基化后强烈改善，表明糖基化治疗性 mAb 作为有效的生物制剂在癌症治疗中的潜力。
