A Chimeric Receptor with NKG2D Specificity Enhances Natural Killer Cell Activation and Killing of Tumor Cells
A Chimeric Receptor with NKG2D Specificity Enhances Natural Killer Cell Activation and Killing of Tumor Cells
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DOI：
10.1158/0008-5472.can-12-3558
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发表时间：
2013-03-15
期刊：
影响因子：
11.2
通讯作者：
Campana, Dario
中科院分区：
文献类型：
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作者：
Chang, Yu-Hsiang;Connolly, John;Campana, Dario
自然杀伤细胞（NK）依靠表面受体来区分健康细胞和癌细胞。我们设计了一种名为NKG2D-DAP10-CD3 zeta的受体，该受体由NK细胞激活分子NKG2D加上2个关键信号分子DAP10和CD3 zeta组成，并评估了其促进癌细胞杀伤的能力。逆转录病毒转导NKG2D- dap10 - cd3 zeta显著增加NK细胞中NKG2D表面的表达，与模拟转导细胞相比，NK细胞对白血病和实体肿瘤细胞系的细胞毒性始终更高。相反，对未转化的血液和间充质细胞的细胞毒性没有增加。NKG2D阻断剂取消了对癌细胞的细胞毒性增益。受体刺激引发信号转导，ifn - γ、GM-CSF、IL-13、MIP-1 α、MIP-1 β、CCL5和tnf - α分泌，细胞毒性颗粒大量释放，持续刺激48小时后仍持续。在小鼠骨肉瘤模型中，表达NKG2D-DAP10-CD3 ζ的NK细胞具有相当大的抗肿瘤活性，而活化的NK细胞则无效。因此，NKG2D-DAP10-CD3 zeta受体的表达可以显著增强NK细胞对多种肿瘤亚型的细胞毒性。电穿孔方法的发展允许受体在大量人类NK细胞中快速表达，促进了这种基于NK的策略的临床翻译，这种策略可能有助于治疗各种癌症。癌症Res;73 (6);1777 - 86。AACR (C) 2012。
Natural killer (NK) cells rely on surface receptors to distinguish healthy cells from cancer cells. We designed a receptor termed NKG2D-DAP10-CD3 zeta that is composed of the NK cell activating molecule NKG2D plus 2 key signaling molecules, DAP10 and CD3 zeta, and evaluated its capacity to promote cancer cell killing. Retroviral transduction of NKG2D-DAP10-CD3 zeta markedly increased NKG2D surface expression in NK cells, which became consistently more cytotoxic than mock-transduced cells against leukemia and solid tumor cell lines. In contrast, there was no increase in cytotoxicity against nontransformed blood and mesenchymal cells. NKG2D blockade abrogated gains in cytotoxicity to cancer cells. Receptor stimulation triggered signal transduction, secretion of IFN-gamma, GM-CSF, IL-13, MIP-1 alpha, MIP-1 beta, CCL5, and TNF-alpha, and massive release of cytotoxic granules, which persisted after 48 hours of continuous stimulation. NKG2D-DAP10-CD3 zeta-expressing NK cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas activated NK cells were ineffective. Thus, the cytotoxic potential of NK cells against a wide spectrum of tumor subtypes could be markedly enhanced by expression of NKG2D-DAP10-CD3 zeta receptors. The development of an electroporation method that permits rapid expression of the receptor in a large number of human NK cells facilitates clinical translation of this NK-based strategy for a generalized cellular therapy that may be useful to treat a wide range of cancers. Cancer Res; 73(6); 1777-86. (C)2012 AACR.