| Literature DB >> 27213690 |
Rebecca B Delconte1,2, Tatiana B Kolesnik1, Laura F Dagley1,2, Jai Rautela1,2, Wei Shi1,2, Eva M Putz3, Kimberley Stannard3, Jian-Guo Zhang1,2, Charis Teh1,2, Matt Firth1,2, Takashi Ushiki1,2, Christopher E Andoniou4, Mariapia A Degli-Esposti4, Phillip P Sharp1,2, Caroline E Sanvitale5, Giuseppe Infusini1, Nicholas P D Liau1,2, Edmond M Linossi1,2, Christopher J Burns1,2, Sebastian Carotta1,2, Daniel H D Gray1,2, Cyril Seillet1,2, Dana S Hutchinson6, Gabrielle T Belz1,2, Andrew I Webb1,2, Warren S Alexander1,2, Shawn S Li7, Alex N Bullock5, Jeffery J Babon1,2, Mark J Smyth3,8, Sandra E Nicholson1,2, Nicholas D Huntington1,2.
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.Entities:
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Year: 2016 PMID： 27213690 DOI： 10.1038/ni.3470
Source DB: PubMed Journal: Nat Immunol ISSN： 1529-2908 Impact factor: 25.606