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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.

Original publication

DOI

10.1038/ni.3470

Type

Journal article

Journal

Nat Immunol

Publication Date

07/2016

Volume

17

Pages

816 - 824

Keywords

Animals, Cell Proliferation, Cytotoxicity, Immunologic, Immunologic Surveillance, Immunotherapy, Interferon-gamma, Interleukin-15, Janus Kinase 1, Killer Cells, Natural, Lymphocyte Activation, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Targeted Therapy, Neoplasms, Signal Transduction, Suppressor of Cytokine Signaling Proteins