NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis
NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis
复制标题
NKp 46受体介导的自然杀伤细胞产生干扰素-γ增加纤维连接蛋白1改变肿瘤结构和控制转移
DOI：
10.1016/j.immuni.2017.12.007
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发表时间：
2018-01-16
期刊：
影响因子：
32.4
通讯作者：
Mandelboim, Ofer
中科院分区：
文献类型：
--
作者：
Glasner, Ariella;Levi, Assi;Mandelboim, Ofer
自然杀伤(NK)细胞是先天的淋巴样细胞，它们在人类肿瘤中的存在与较好的预后相关。然而，NK细胞在体内控制肿瘤的机制尚不清楚。在这里，我们使用反射共聚焦显微镜(RCM)成像技术在人类和小鼠体内显示肿瘤的结构。我们证明了通过NK细胞受体NKp46(人)和Ncr1(小鼠)的信号诱导瘤内NK细胞分泌干扰素-γ。NKp46和Ncr1介导的干扰素-γ的产生导致肿瘤中细胞外基质蛋白FN1的表达增加，从而改变了原发肿瘤的结构，减少了转移的形成。在荷瘤小鼠体内注射干扰素-γ或在小鼠NK细胞中过表达Ncr1基因可减少肿瘤转移。因此，我们定义了一种NK细胞介导的体内转移控制机制，这可能有助于开发NK细胞依赖的癌症治疗。
Natural killer (NK) cells are innate lymphoid cells, and their presence within human tumors correlates with better prognosis. However, the mechanisms by which NK cells control tumors in vivo are unclear. Here, we used reflectance confocal microscopy (RCM) imaging in humans and in mice to visualize tumor architecture in vivo. We demonstrated that signaling via the NK cell receptor NKp46 (human) and Ncr1 (mouse) induced interferon-gamma (IFN-gamma) secretion from intratumoral NK cells. NKp46-and Ncr1-mediated IFN-gamma production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation. Injection of IFN-gamma into tumor-bearing mice or transgenic overexpression of Ncr1 in NK cells in mice resulted in decreased metastasis formation. Thus, we have defined a mechanism of NK cell-mediated control of metastases in vivo that may help develop NK cell-dependent cancer therapies.