title: Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis.
abstract: The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis.Cish-deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged inCish-deficient mice. The combination ofCishdeficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy.
authors.affiliation: Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Medicine, The University of Queensland, Herston, Queensland, Australia.
authors.forename: Camille
authors.initials: C
authors.lastname: Guillerey
authors.affiliation: Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kos
authors.affiliation: Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stannard
authors.affiliation: Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Miles
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: Department of Immunology, Juntendo University School of Medicine , Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
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.initials: ND
authors.lastname: Huntington
authors.affiliation: Immunology of Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Medicine, The University of Queensland, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
keywords: Cancer; NK cells; cytokine signaling; immunotherapy; metastasis