title: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Delconte
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Kolesnik
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Dagley
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Jai
authors.initials: J
authors.lastname: Rautela
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Immunology in Cancer and Infection Laboratory QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Eva M
authors.identifier: 0000-0002-9990-4477
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Immunology in Cancer and Infection Laboratory QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stannard
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Charis
authors.initials: C
authors.lastname: Teh
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Matt
authors.initials: M
authors.lastname: Firth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ushiki
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia and Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia and Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Sharp
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford, Oxford, UK.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Sanvitale
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Infusini
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Nicholas P D
authors.initials: NP
authors.lastname: Liau
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Edmond M
authors.initials: EM
authors.lastname: Linossi
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Carotta
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Daniel H D
authors.initials: DH
authors.lastname: Gray
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Cyril
authors.initials: C
authors.lastname: Seillet
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Hutchinson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Webb
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium (SGC), University of Oxford, Oxford, UK.
authors.forename: Alex N
authors.identifier: 0000-0001-6757-0436
authors.initials: AN
authors.lastname: Bullock
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Jeffery J
authors.identifier: 0000-0002-5408-6239
authors.initials: JJ
authors.lastname: Babon
authors.affiliation: Immunology in Cancer and Infection Laboratory QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Victoria, Australia.
authors.forename: Nicholas D
authors.identifier: 0000-0002-5267-7211
authors.initials: ND
authors.lastname: Huntington
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007157:Immunologic Surveillance; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D015398:Signal Transduction / Q000235:genetics; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007371:Interferon-gamma; D019409:Interleukin-15; D053613:Janus Kinase 1; D050826:Suppressor of Cytokine Signaling Proteins; C507904:JAK1 protein, human