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. 2016 Jul;17(7):816-24.
doi: 10.1038/ni.3470. Epub 2016 May 23.

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

Rebecca B Delconte  1   2 , Tatiana B Kolesnik  1 , Laura F Dagley  1   2 , Jai Rautela  1   2 , Wei Shi  1   2 , Eva M Putz  3 , Kimberley Stannard  3 , Jian-Guo Zhang  1   2 , Charis Teh  1   2 , Matt Firth  1   2 , Takashi Ushiki  1   2 , Christopher E Andoniou  4 , Mariapia A Degli-Esposti  4 , Phillip P Sharp  1   2 , Caroline E Sanvitale  5 , Giuseppe Infusini  1 , Nicholas P D Liau  1   2 , Edmond M Linossi  1   2 , Christopher J Burns  1   2 , Sebastian Carotta  1   2 , Daniel H D Gray  1   2 , Cyril Seillet  1   2 , Dana S Hutchinson  6 , Gabrielle T Belz  1   2 , Andrew I Webb  1   2 , Warren S Alexander  1   2 , Shawn S Li  7 , Alex N Bullock  5 , Jeffery J Babon  1   2 , Mark J Smyth  3   8 , Sandra E Nicholson  1   2 , Nicholas D Huntington  1   2
Affiliations

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

Rebecca B Delconte et al. Nat Immunol. 2016 Jul.

Erratum in

  • Author Correction: 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 NPD, Linossi EM, Burns CJ, Carotta S, Gray DHD, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, Huntington ND. Delconte RB, et al. Nat Immunol. 2024 Feb;25(2):371-372. doi: 10.1038/s41590-023-01714-8. Nat Immunol. 2024. PMID: 38087084 No abstract available.

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.

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