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

被引：282

作者：

Delconte, Rebecca B. ^{[1
,2
]}

Kolesnik, Tatiana B. ^{[1
]}

Dagley, Laura F. ^{[1
,2
]}

Rautela, Jai ^{[1
,2
]}

Shi, Wei ^{[1
,2
]}

Putz, Eva M. ^{[3
]}

Stannard, Kimberley ^{[3
]}

Zhang, Jian-Guo ^{[1
,2
]}

Teh, Charis ^{[1
,2
]}

Firth, Matt ^{[1
,2
]}

Ushiki, Takashi ^{[1
,2
]}

Andoniou, Christopher E. ^{[4
,5
]}

Degli-Esposti, Mariapia A. ^{[4
,5
]}

Sharp, Phillip P. ^{[1
,2
]}

Sanvitale, Caroline E. ^{[6
]}

Infusini, Giuseppe ^{[1
]}

Liau, Nicholas P. D. ^{[1
,2
]}

Linossi, Edmond M. ^{[1
,2
]}

Burns, Christopher J. ^{[1
,2
]}

Carotta, Sebastian ^{[1
,2
]}

Gray, Daniel H. D. ^{[1
,2
]}

Seillet, Cyril ^{[1
,2
]}

Hutchinson, Dana S. ^{[7
]}

Belz, Gabrielle T. ^{[1
,2
]}

Webb, Andrew I. ^{[1
,2
]}

Alexander, Warren S. ^{[1
,2
]}

Li, Shawn S. ^{[8
,9
]}

Bullock, Alex N. ^{[6
]}

Babon, Jeffery J. ^{[1
,2
]}

Smyth, Mark J. ^{[3
,10
]}

Nicholson, Sandra E. ^{[1
,2
]}

Huntington, Nicholas D. ^{[1
,2
]}

机构：

[1] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

[2] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia

[3] QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Herston, Qld, Australia

[4] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Immunol & Virol Program, Nedlands, WA 6009, Australia

[5] Lions Eye Inst, Ctr Expt Immunol, Nedlands, WA, Australia

[6] Univ Oxford, Struct Genom Consortium, Oxford, England

[7] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic, Australia

[8] Univ Western Ontario, Schulich Sch Med & Dent, Dept Biochem, London, ON, Canada

[9] Univ Western Ontario, Schulich Sch Med & Dent, Siebens Drake Med Res Inst, London, ON, Canada

[10] Univ Queensland, Sch Med, Herston, Qld, Australia

来源：

NATURE IMMUNOLOGY | 2016年 / 17卷 / 07期

基金：

澳大利亚国家健康与医学研究理事会; 奥地利科学基金会; 澳大利亚研究理事会; 加拿大创新基金会; 英国惠康基金; 英国医学研究理事会;

关键词：

NATURAL-KILLER-CELLS; T-CELLS; ANTI-PD-L1; ANTIBODY; CANCER-THERAPY; PROTEIN; SUPPRESSION; ACTIVATION; IPILIMUMAB; BINDS; GENE;

D O I：

10.1038/ni.3470

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：816 / +

页数：13

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