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

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.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

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,Se

doi

10.1038/ni.3470

subject

Has Abstract

pub_date

2016-07-01 00:00:00

pages

816-24

issue

7

eissn

1529-2908

issn

1529-2916

pii

ni.3470

journal_volume

17

pub_type

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