Arnon Tal I, Markel Gal, Bar-Ilan Ahuva, Hanna Jacob, Fima Eyal, Benchetrit Fabrice, Galili Ruth, Cerwenka Adelheid, Benharroch Daniel, Sion-Vardy Netta, Porgador Angel, Mandelboim Ofer
Division of Biology, California Institute of Technology, Pasadena, California, United States of America.
PLoS One. 2008 May 14;3(5):e2150. doi: 10.1371/journal.pone.0002150.
The natural cytotoxic receptors (NCRs) are a unique set of activating proteins expressed mainly on the surface of natural killer (NK) cells. The NCRs, which include three members; NKp46, NKp44 and NKp30, are critically involved in NK cytotoxicity against different targets, including a wide range of tumor cells derived from various origins. Even though the tumor ligands of the NCRs have not been identified yet, the selective manner by which these receptors target tumor cells may provide an excellent basis for the development of novel anti-tumor therapies. To test the potential use of the NCRs as anti-tumor agents, we generated soluble NCR-Ig fusion proteins in which the constant region of human IgG1 was fused to the extracellular portion of the receptor. We demonstrate, using two different human prostate cancer cell lines, that treatment with NKp30-Ig, dramatically inhibits tumor growth in vivo. Activated macrophages were shown to mediate an ADCC response against the NKp30-Ig coated prostate cell lines. Finally, the Ig fusion proteins were also demonstrated to discriminate between benign prostate hyperplasia and prostate cancer. This may provide a novel diagnostic modality in the difficult task of differentiating between these highly common pathological conditions.
自然细胞毒性受体（NCRs）是一组独特的激活蛋白，主要表达于自然杀伤（NK）细胞表面。NCRs包括三个成员：NKp46、NKp44和NKp30，它们在NK细胞对不同靶标的细胞毒性中起关键作用，这些靶标包括多种来源的广泛肿瘤细胞。尽管NCRs的肿瘤配体尚未确定，但这些受体靶向肿瘤细胞的选择性方式可能为新型抗肿瘤疗法的开发提供良好基础。为了测试NCRs作为抗肿瘤药物的潜在用途，我们生成了可溶性NCR-Ig融合蛋白，其中人IgG1的恒定区与受体的细胞外部分融合。我们使用两种不同的人前列腺癌细胞系证明，用NKp30-Ig处理可显著抑制体内肿瘤生长。已表明活化的巨噬细胞介导针对NKp30-Ig包被的前列腺癌细胞系的抗体依赖的细胞介导的细胞毒性（ADCC）反应。最后，还证明了Ig融合蛋白能够区分良性前列腺增生和前列腺癌。这可能为区分这些高度常见的病理状况这一艰巨任务提供一种新型诊断方法。
