Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells
Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells
复制标题
人融合 NKG2D-IL-15 蛋白通过 NK 细胞的招募和激活来控制异种移植人胃癌
DOI：
10.1038/cmi.2015.81
复制
发表时间：
2017-03-01
影响因子：
24.1
通讯作者：
Gong, Weijuan
中科院分区：
文献类型：
--
作者：
Chen, Yan;Chen, Bei;Gong, Weijuan
白细胞介素（IL）-15在自然杀伤（NK）和CD 8 + T细胞增殖和功能中起重要作用，并且比IL-2更有效地用于肿瘤免疫治疗。通过邻近细胞的IL-15的反式呈递对于NK细胞活化比其可溶性IL-15更有效。在这项研究中，融合蛋白dsNKG 2D-IL-15，其中包括两个相同的细胞外结构域的人NKG 2D耦合到人IL-15通过一个接头，在大肠杆菌工程。DsNKG 2D-IL-15可通过两个NKG 2D结构域与人肿瘤细胞的主要组织相容性复合物I类链相关蛋白A（云母）有效结合，并将IL-15反式提呈给NK或CD 8 + T细胞。我们将人胃癌细胞（SGC-7901）移植到裸鼠体内，并将异位表达云母的小鼠黑色素瘤细胞（B16 BL 6-云母）移植到C57 BL/6小鼠体内。然后，我们研究了dsNKG 2D-IL-15在两种异种移植肿瘤模型中介导的抗肿瘤作用。人dsNKG 2D-IL-15在抑制胃癌生长方面表现出比IL-15更高的效率。基于体内实时成像，外源性人dsNKG 2D-IL-15集中分布在小鼠肿瘤组织中。人dsNKG 2D-IL-15治疗后，将外周血单个核细胞注射到荷人胃癌的裸鼠中后，浸润到肿瘤组织中的人CD 56+细胞的频率显著增加。人dsNKG 2D-IL-15还通过激活和募集小鼠NK和CD 8 +T细胞来延迟移植的黑素瘤（B16 BL 6-云母）的生长。人dsNKG 2D-IL-15在C57 BL/6小鼠中的抗黑色素瘤作用主要通过小鼠NK细胞的体内耗竭而降低。这些数据突出了人dsNKG 2D-IL-15用于肿瘤治疗的潜在用途。
Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.