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

Rebecca B Delconte, Tatiana B Kolesnik, Laura F Dagley, Jai Rautela, Wei Shi, Eva M Putz, Kimberley Stannard, Jian-Guo Zhang, Charis Teh, Matt Firth, Takashi Ushiki, Christopher E Andoniou, Mariapia A Degli-Esposti, Phillip P Sharp, Caroline E Sanvitale, Giuseppe Infusini, Nicholas P D Liau, Edmond M Linossi, Christopher J Burns, Sebastian Carotta, Daniel H D Gray, Cyril Seillet, Dana S Hutchinson, Gabrielle T Belz, Andrew I Webb, Warren S Alexander, Shawn S Li, Alex N Bullock, Jeffery J Babon, Mark J Smyth, Sandra E Nicholson, Nicholas D Huntington

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.