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

• Published in: Nature immunology Vol. 17; no. 7; pp. 816 - 824
• Main Authors: Delconte, Rebecca B, Kolesnik, Tatiana B, Dagley, Laura F, Rautela, Jai, Shi, Wei, Putz, Eva M, Stannard, Kimberley, Zhang, Jian-Guo, Teh, Charis, Firth, Matt, Ushiki, Takashi, Andoniou, Christopher E, Degli-Esposti, Mariapia A, Sharp, Phillip P, Sanvitale, Caroline E, Infusini, Giuseppe, Liau, Nicholas P D, Linossi, Edmond M, Burns, Christopher J, Carotta, Sebastian, Gray, Daniel H D, Seillet, Cyril, Hutchinson, Dana S, Belz, Gabrielle T, Webb, Andrew I, Alexander, Warren S, Li, Shawn S, Bullock, Alex N, Babon, Jeffery J, Smyth, Mark J, Nicholson, Sandra E, Huntington, Nicholas D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2016; Nature Publishing Group
• Subjects: 13/21; 14/35; 631/250/2504/2506; 631/45/275; 692/699/67/580/1884; 82; 82/58; Animals; Biomedicine; Cancer; Cancer immunotherapy; Cancer metastasis; Carcinogenesis; Carcinoma in situ; Care and treatment; Cell proliferation; Cell Proliferation - genetics; Cellular signal transduction; Cytokines; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Diagnosis; Dosage and administration; Enzymatic activity; Genetic aspects; Health aspects; Immunity; Immunologic Surveillance; Immunology; Immunotherapy; Immunotherapy - methods; Infectious Diseases; Interferon-gamma - metabolism; Interleukin 15; Interleukin-15 - metabolism; Janus kinase; Janus Kinase 1 - metabolism; Killer cells; Killer Cells, Natural - immunology; Kinases; Lymphocyte Activation - genetics; Melanoma; Melanoma, Experimental; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Natural killer cells; Neoplasms - immunology; Neoplasms - therapy; Prostate cancer; Proteasomes; Protein-tyrosine kinase; Signal Transduction - genetics; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Tumors; Tyrosine; γ-Interferon
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3470

IL-15-driven NK cells mediate anti-tumor immunity, but how IL-15 is negatively regulated remains unclear. Huntington and colleagues find that CIS, a member of the suppressor of cytokine signaling family, suppresses the response to IL-15 and, as a result, CIS-deficient mice are more resistant to cancer metastasis. 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.