The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University Medical School, Jerusalem, Israel.
Photodermatosis Clinic, Department of Dermatology, Rabin Medical Center, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Immunity. 2018 Jan 16;48(1):107-119.e4. doi: 10.1016/j.immuni.2017.12.007. Epub 2018 Jan 9.
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-γ (IFN-γ) secretion from intratumoral NK cells. NKp46- and Ncr1-mediated IFN-γ 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-γ 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.
自然杀伤 (NK) 细胞是先天淋巴细胞，其存在于人类肿瘤中与更好的预后相关。然而，NK 细胞在体内控制肿瘤的机制尚不清楚。在这里，我们使用人体和小鼠中的反射共聚焦显微镜 (RCM) 成像来可视化体内肿瘤结构。我们证明，通过 NK 细胞受体 NKp46（人）和 Ncr1（小鼠）的信号传导诱导肿瘤内 NK 细胞分泌干扰素-γ (IFN-γ)。NKp46 和 Ncr1 介导的 IFN-γ 产生导致肿瘤中细胞外基质蛋白纤维连接蛋白 1 (FN1) 的表达增加，改变了原发性肿瘤结构，并导致转移形成减少。向荷瘤小鼠注射 IFN-γ 或在小鼠中过表达 NK 细胞中的 Ncr1 导致转移形成减少。因此，我们已经定义了一种 NK 细胞介导的体内转移控制机制，这可能有助于开发依赖 NK 细胞的癌症疗法。
