SOCS protein regulation of NK cell-mediated tumor immunity

RB Delconte1,2, TB Kolesnik1, LF Dagley1,2, J Rautela1,2, EL Linossi1,2, EM Putz3, MJ Smyth3,4, JJ Babon1,2, ND Huntington1,2 and SE Nicholson1,2

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC
  2. Department of Medical Biology, The University of Melbourne, VIC, Australia
  3. Immunology in Cancer and Infection Laboratory QIMR Berghofer Medical Research Institute, Herston, QLD
  4. School of Medicine, University of Queensland, Herston, QLD, Australia

Natural killer (NK) cells have evolved to detect and kill aberrant cells. NK cell function is governed by the cytokine interleukin (IL)-15 and the detection of foreign and self-ligands, which together generate an integrated intracellular signal cascade. There has been a great deal of interest in understanding the inhibitory signals that curb NK cell responses, yet we still do not understand how IL-15 signalling is switched off. The Suppressor of cytokine signalling (SOCS) proteins are induced in response to JAK/STAT activation and act to limit the extent of cytokine receptor signalling. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical SOCS protein regulating IL-15 signalling 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 superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. Cish–/– mice were resistant to experimental melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. This study has uncovered a potent checkpoint in NK cell-mediated tumour immunity.