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Nat Immunol. 2016 Jul;17(7):816-24. doi: 10.1038/ni.3470. Epub 2016 May 23.

CIS is a potent checkpoint in NK cell-mediated tumor immunity.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
2
Department of Medical Biology, The University of Melbourne, Victoria, Australia.
3
Immunology in Cancer and Infection Laboratory QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
4
Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia and Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia.
5
Structural Genomics Consortium (SGC), University of Oxford, Oxford, UK.
6
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
7
Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
8
School of Medicine, University of Queensland, Herston, Queensland, Australia.

Abstract

The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

PMID:
27213690
DOI:
10.1038/ni.3470
[Indexed for MEDLINE]

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