Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas
Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas
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DOI：
10.1073/pnas.0804788105
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发表时间：
2008-11-11
影响因子：
11.1
通讯作者：
Charo, Jehad
中科院分区：
文献类型：
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作者：
Kruschinski, Anna;Moosmann, Andreas;Charo, Jehad
NIK细胞是肿瘤过继免疫治疗的有希望的效应物，特别是当考虑靶向MHC I类低或阴性肿瘤时。然而，NK细胞不能对许多肿瘤作出反应，这对于非造血肿瘤如癌或黑色素瘤尤其如此，即使当这些细胞失去MHC I类表面表达时。因此，我们通过HER-2特异性激活嵌合受体的基因转移靶向原代人NK细胞，HER-2在癌细胞上经常过表达。我们发现，这些靶向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以及脱粒所示。这种特异性反应的程度与肿瘤细胞上HER-2的表达水平相关。最后，这些受体转导的NK细胞，而不是它们的模拟物转导的对应物，有效地根除了RAG 2敲除小鼠中的肿瘤细胞，如通过体内成像可视化的。总之，这些结果表明，这种活化受体的表达超越了原代人NK细胞中的抑制信号，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。
NIK cells are promising effectors for tumor adoptive immunotherapy, 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.