Transcriptomics,Genomics

Dataset Information

166

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


ABSTRACT: Natural killer (NK) cells have evolved to detect and kill aberrant cells with this activity being governed by the cytokine interleukin (IL)-15 and foreign and self-ligands. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical negative regulator of IL-15 signalling 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 superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. This was associated with enhanced JAK/STAT signalling in Cish-deleted NK cells. 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. This study has uncovered a potent checkpoint in NK cell-mediated tumour immunity and holds promise for novel immunotherapies directed at blocking CIS function. Overall design: Transcriptional profiling of ex vivo and in vitro CIS-/- nature killer cells

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Wei Shi  

PROVIDER: GSE79409 | GEO | 2016-05-20

SECONDARY ACCESSION(S): PRJNA315771

REPOSITORIES: GEO

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Publications

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

Delconte Rebecca B RB   Kolesnik Tatiana B TB   Dagley Laura F LF   Rautela Jai J   Shi Wei W   Putz Eva M EM   Putz Eva M EM   Stannard Kimberley K   Zhang Jian-Guo JG   Teh Charis C   Firth Matt M   Ushiki Takashi T   Andoniou Christopher E CE   Degli-Esposti Mariapia A MA   Sharp Phillip P PP   Sanvitale Caroline E CE   Infusini Giuseppe G   Liau Nicholas P D NP   Linossi Edmond M EM   Burns Christopher J CJ   Carotta Sebastian S   Gray Daniel H D DH   Seillet Cyril C   Hutchinson Dana S DS   Belz Gabrielle T GT   Webb Andrew I AI   Alexander Warren S WS   Li Shawn S SS   Bullock Alex N AN   Babon Jeffery J JJ   Smyth Mark J MJ   Nicholson Sandra E SE   Huntington Nicholas D ND  

Nature immunology 20160523 7


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  ...[more]

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