CIS is a potent checkpoint in NK cell–mediated tumor immunity Academic Article uri icon


  • 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.


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

publication date

  • July 2016

has subject area