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

Author(s): 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;
Details: Publication Year 2016,Volume 17,Issue #7,Page 816-824
Journal Title: Nat Immunol
Publication Type: Journal Article
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-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.
Publisher: NPG
Research Division(s): Molecular Genetics Of Cancer; Structural Biology; Chemical Biology; Cancer And Haematology; Bioinformatics; Inflammation; Molecular Immunology; Systems Biology And Personalised Medicine
PubMed ID: 27213690
Publisher's Version: https://doi.org/10.1038/ni.3470
NHMRC Grants: NHMRC/1027472, NHMRC/1047903, NHMRC/1016647, NHMRC/1049407, NHMRC/1066770, NHMRC/1078763, NHMRC/1058344, NHMRC/1090236, NHMRC/1089072,
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Documents: Delconte et al Nature Immunol 2016.pdf - (15.35MB, application/pdf)

Creation Date: 2016-06-16 10:27:04

Last Modified: 2018-06-04 09:05:44