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Immunity. 2018 Jan 16;48(1):107-119.e4. doi: 10.1016/j.immuni.2017.12.007. Epub 2018 Jan 9.

NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis.

Author information

1
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.
2
Photodermatosis Clinic, Department of Dermatology, Rabin Medical Center, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
3
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
4
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
5
Medical Screening Institute, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Department of Pathology, Hadassah Medical Organization, The Hebrew University Medical Center, Jerusalem, Israel.
7
Department of Dermatology, Hadassah-Hebrew University Medical School, Jerusalem, Israel.
8
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
9
Department of Histology and Embryology Center for Proteomics, Faculty of Medicine, University of Rijeka, B. Branchetta, Rijeka, Croatia.
10
Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany.
11
Center of Clinical Investigations and U1015 INSERM, Gustave Roussy Cancer Campus, University Paris Saclay, Villejuif-Grand-Paris, France.
12
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. Electronic address: oferm@ekmd.huji.ac.il.

Abstract

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.

KEYWORDS:

FN1; IFN-γ; NKp46; Ncr1; RCM imaging; tumor metastases

PMID:
29329948
DOI:
10.1016/j.immuni.2017.12.007
[Indexed for MEDLINE]
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