Oral Presentation 22nd Annual Lorne Proteomics Symposium 2017

CIS is a potent checkpoint in NK cell-mediated tumor immunity (#2)

Laura F Dagley 1 2 , Rebecca B Delconte 1 2 , Tatiana B Kolesnik 1 2 , Jai Rautela 1 2 , Wei Shi 1 2 , Eva M Putz 3 , Kimberly Stannard 3 , Jian-Guo Zhang 1 2 , Charis Teh 1 2 , Matt Firth 1 2 , Takashi Ushiki 1 2 , Christopher E Andoniou 4 , Mariapia A Degli-Esposti 4 , Phillip P Sharp 1 2 , Caroline E Sanvitale 5 , Giuseppe Infusini 1 2 , Nicholas P.D. Liau 1 2 , Edmond M Linossi 1 2 , Christopher J Burns 1 2 , Sebastian Carotta 1 2 , Daniel H.D. Gray 1 2 , Cyrill Seillet 1 2 , Dana S Hutchinson 6 , Gabrielle T Belz 1 2 , Andrew I Webb 1 2 , Warren S Alexander 1 2 , Shawn S Li 7 , Alex N Bullock 5 , Jeffrey J Babon 1 2 , Mark J Smyth 3 8 , Sandra E Nicholson 1 2 , Nicholas D Huntington 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
  3. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  4. Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia and Centre for Experimental Immunology, Nedlands, WA, Australia
  5. Structural Genomics Consortium (SGC), University of Oxford, Oxford, OX3 7DQ, UK
  6. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  7. Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
  8. School of Medicine, University of Queensland, Herston, QLD, Australia

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. Here we have identified CIS (encoded by Cish) as the 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 towards 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. A mass spectrometry–based approach quantifying changes in active JAK levels was used to confirm the elevated JAK1 activity and to examine the selectivity of the CIS-deficient effects. Cish−/− mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. This study has uncovered a potent intracellular checkpoint in NK cell-mediated tumor immunity and holds promise for novel cancer immunotherapies directed at blocking CIS function.

Efforts are now underway to map the precise interactions between CIS and JAK1 in order to better understand how the complex can be targeted by small molecules to improve the NK cells' response to the growth factor and help patients fight cancer with their own immune system. We are using cross linking mass spectrometry to define the CIS/JAK1 binding interface.

  1. Delconte, R.B. et al. Nat Immunol 17, 816-824 (2016).