Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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