| First Author | Delconte RB | Year | 2016 |
| Journal | Nat Immunol | Volume | 17 |
| Issue | 7 | Pages | 816-24 |
| PubMed ID | 27213690 | Mgi Jnum | J:259141 |
| Mgi Id | MGI:6142346 | Doi | 10.1038/ni.3470 |
| Citation | Delconte RB, et al. (2016) CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol 17(7):816-24 |
| abstractText | 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-gamma 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. |
