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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Engineering Antigen-specific Primary Human Nk Cells Against Her-2 Positive Carcinomas
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Engineering Antigen-specific Primary Human Nk Cells Against Her-2 Positive Carcinomas

机译：针对Her-2阳性癌的工程抗原特异性原代人Nk细胞。

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NK cells are promising effectors for tumor adoptive immunother-apy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these cells lose MHC class I surface expression. Therefore, we targeted primary human NK cells by gene transfer of an activating chimeric receptor specific for HER-2, which is frequently overexpressed on carcinomas. We found that these targeted NK cells were specifically activated upon recognition of all evaluated HER-2 positive tumor cells, including autologous targets, as indicated by high levels of cytokine secretion as well as degranulation. The magnitude of this specific response correlated with the level of HER-2 expression on the tumor cells. Finally, these receptor transduced NK cells, but not their mock transduced counterpart, efficiently eradicated tumor cells in RAG2 knockout mice as visualized by in vivo imaging. Taken together, these results indicate that the expression of this activating receptor overrides inhibitory signals in primary human NK cells and directs them specifically toward HER-2 expressing tumor cells both in vitro and in vivo.
机译：NK细胞是肿瘤过继免疫治疗的有希望的效应子，特别是在考虑靶向I类MHC低或阴性肿瘤时。但是，NK细胞不能对许多肿瘤产生反应，即使非造血性肿瘤，例如癌或黑色素瘤，即使这些细胞失去I类MHC表面表达，情况也是如此。因此，我们通过对HER-2特异的活化嵌合受体进行基因转移来靶向原代人NK细胞，该受体通常在癌症中过表达。我们发现，这些靶向的NK细胞在识别所有评估的HER-2阳性肿瘤细胞（包括自体靶标）后被特异性激活，如高水平的细胞因子分泌和脱粒所表明的。这种特异性反应的程度与肿瘤细胞上HER-2表达的水平有关。最后，这些受体转导的NK细胞，而不是它们的模拟转导的NK细胞，通过体内成像显示，可以有效根除RAG2基因敲除小鼠的肿瘤细胞。综上所述，这些结果表明该活化受体的表达在原代人NK细胞中优于抑制信号，并在体外和体内将它们特异性地导向表达HER-2的肿瘤细胞。

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