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

Authors

Rebecca B. Delconte, Walter and Eliza Hall Institute of Medical Research
Tatiana B. Kolesnik, Walter and Eliza Hall Institute of Medical Research
Laura F. Dagley, Walter and Eliza Hall Institute of Medical Research
Jai Rautela, Walter and Eliza Hall Institute of Medical Research
Wei Shi, Walter and Eliza Hall Institute of Medical Research
Eva M. Putz, QIMR Berghofer Medical Research Institute
Kimberley Stannard, QIMR Berghofer Medical Research Institute
Jian Guo Zhang, Walter and Eliza Hall Institute of Medical Research

Document Type

Article

Publication Date

6-21-2016

Journal

Nature Immunology

Volume

17

Issue

7

First Page

816

Last Page

824

URL with Digital Object Identifier

10.1038/ni.3470

Abstract

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.