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


Delconte, RB; Kolesnik, TB; Dagley, LF; Rautela, J; Shi, W; Putz, EM; Stannard, K; Zhang, JG; Teh, C; Firth, M; Ushiki, T; Andoniou, CE; Degli-Esposti, MA; Sharp, PP; Sanvitale, CE; Infusini, G; Liau, NP; Linossi, EM; Burns, CJ; Carotta, S; Gray, DH; Seillet, C; Hutchinson, DS; Belz, GT; Webb, AI; Alexander, WS; Li, SS; Bullock, AN; Babon, JJ; Smyth, MJ; Nicholson, SE; Huntington, ND
2016
Nat Immunol
Journal Article
17
7
816-824
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-gamma 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.
NPG
Molecular Immunology; Inflammation; Systems Biology and Personalised Medicine; Bioinformatics; Cancer and Haematology; Molecular Genetics of Cancer; Structural Biology; Chemical Biology
10.1038/ni.3470
27213690
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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