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

Delconte, Rebecca B., Kolesnik, Tatiana B., Dagley, Laura F., Rautela, Jai, Shi, Wei, Putz, Eva M., Stannard, Kimberley, Zhang, Jian-Guo, Teh, Charis, Firth, Matt, Ushiki, Takashi, Andoniou, Christopher E., Degli-Esposti, Mariapia A., Sharp, Phillip P., Sanvitale, Caroline E., Infusini, Giuseppe, Liau, Nicholas P. D., Linossi, Edmond M., Burns, Christopher J., Carotta, Sebastian, Gray, Daniel H. D., Seillet, Cyril, Hutchinson, Dana S., Belz, Gabrielle T., Webb, Andrew I., Alexander, Warren S., Li, Shawn S., Bullock, Alex N., Babon, Jeffery J., Smyth, Mark J., Nicholson, Sandra E. and Huntington, Nicholas D. (2016) CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nature Immunology, 17 7: 816-824. doi:10.1038/ni.3470

Author Delconte, Rebecca B.
Kolesnik, Tatiana B.
Dagley, Laura F.
Rautela, Jai
Shi, Wei
Putz, Eva M.
Stannard, Kimberley
Zhang, Jian-Guo
Teh, Charis
Firth, Matt
Ushiki, Takashi
Andoniou, Christopher E.
Degli-Esposti, Mariapia A.
Sharp, Phillip P.
Sanvitale, Caroline E.
Infusini, Giuseppe
Liau, Nicholas P. D.
Linossi, Edmond M.
Burns, Christopher J.
Carotta, Sebastian
Gray, Daniel H. D.
Seillet, Cyril
Hutchinson, Dana S.
Belz, Gabrielle T.
Webb, Andrew I.
Alexander, Warren S.
Li, Shawn S.
Bullock, Alex N.
Babon, Jeffery J.
Smyth, Mark J.
Nicholson, Sandra E.
Huntington, Nicholas D.
Title CIS is a potent checkpoint in NK cell-mediated tumor immunity
Journal name Nature Immunology   Check publisher's open access policy
ISSN 1529-2916
Publication date 2016-07
Year available 2016
Sub-type Article (original research)
DOI 10.1038/ni.3470
Open Access Status Not yet assessed
Volume 17
Issue 7
Start page 816
End page 824
Total pages 9
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted 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.
Keyword Natural killer (NK) cells
Cytokine-inducible SH2-containing protein (CIS)
T cell function
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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