Immunity
Volume 48, Issue 1, 16 January 2018, Pages 107-119.e4
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Article
NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis

https://doi.org/10.1016/j.immuni.2017.12.007Get rights and content
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Highlights

  • NKp46 expression on NK cells controls growth of melanoma and carcinoma metastases

  • In the absence of NKp46, tumor architectural properties indicate an aggressive phenotype

  • NK cell NKp46-mediated IFN-γ production controls tumor structure via FN1 induction

  • IFN-γ treatment or Ncr1 overexpression in tumor-bearing mice decreases tumor metastases

Summary

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

NKp46
Ncr1
RCM imaging
IFN-γ
FN1
tumor metastases

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These authors contributed equally

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