NK cell‐mediated anti‐leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti‐CD20 scfv chimeric protein
NK cell‐mediated anti‐leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti‐CD20 scfv chimeric protein
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DOI：
10.1002/eji.201847550
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发表时间：
2018-08
影响因子：
5.4
通讯作者：
Y. Zou;Weiguang Luo;Jing Guo;Q. Luo;Mi Deng;Zhigang Lu;Yi Fang;C. Zhang
中科院分区：
文献类型：
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作者：
Y. Zou;Weiguang Luo;Jing Guo;Q. Luo;Mi Deng;Zhigang Lu;Yi Fang;C. Zhang
NK细胞是重要的先天性细胞毒性淋巴细胞，具有治疗白血病的潜力。NK细胞上NKG2D受体的结合增强了靶细胞毒性。在这里，我们产生了由NKG2D配体云母的胞外结构域和抗CD20单链可变片段（scFv）组成的融合蛋白。该重组蛋白能够结合NK细胞和CD20+肿瘤细胞。利用我们开发的人NKG2D报告细胞系统，我们发现该融合蛋白可以用云母胞外结构域修饰CD20+肿瘤细胞，并通过NKG2D激活NK。我们进一步证明，这种蛋白质可以特异性地诱导NK细胞系（NKL）和原代NK细胞裂解CD20+白血病细胞的能力。此外，我们发现靶细胞中表面HLA I类表达的下调改善了NKL介导的杀伤。我们的研究结果表明，这种重组蛋白特异性地裂解白血病细胞的NK细胞，这可能导致开发一种新的策略，用于治疗白血病和其他肿瘤。
NK cells are important innate cytotoxic lymphocytes that have potential in treatment of leukemia. Engagement of NKG2D receptor on NK cells enhances the target cytotoxicity. Here, we produced a fusion protein consisting of the extracellular domain of the NKG2D ligand MICA and the anti‐CD20 single‐chain variable fragment (scfv). This recombinant protein is capable of binding both NK cells and CD20+ tumor cells. Using a human NKG2D reporter cell system we developed, we showed that this fusion protein could decorate CD20+ tumor cells with MICA extracellular domain and activate NK through NKG2D. We further demonstrated that this protein could specifically induce the ability of a NK cell line (NKL) and primary NK cells to lyse CD20+ leukemia cells. Moreover, we found that downregulation of surface HLA class I expression in the target cells improved NKL‐mediated killing. Our results demonstrated that this recombinant protein specifically lyses leukemia cells by NK cells, which may lead to development of a novel strategy for treating leukemia and other tumors.