CIS is a potent checkpoint in NK cell mediated tumor immunity
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 g 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.
Nature Immunology