CIS is a potent checkpoint in NK cell-mediated tumor immunity
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
WEHI 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
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-06-16 10:27:04
Last Modified: 2018-06-04 09:05:44
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