Journal article

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

Rebecca B Delconte, Tatiana B Kolesnik, Laura F Dagley, Jai Rautela, Wei Shi, Eva M Putz, Kimberley Stannard, Jian-Guo Zhang, Charis Teh, Matt Firth, Takashi Ushiki, Christopher E Andoniou, Mariapia A Degli-Esposti, Phillip P Sharp, Caroline E Sanvitale, Giuseppe Infusini, Nicholas PD Liau, Edmond M Linossi, Christopher J Burns, Sebastian Carotta Show all



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 i..

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Awarded by National Health and Medical Research Council (NHMRC) of Australia

Awarded by NHMRC

Awarded by Austrian Science Fund (FWF)

Awarded by AbbVie

Awarded by Bayer PHARMA AG

Awarded by Boehringer Ingelheim

Awarded by Canada Foundation for Innovation

Awarded by Canadian Institutes for Health Research

Awarded by Genome Canada

Awarded by GlaxoSmithKline

Awarded by Janssen

Awarded by Lilly Canada

Awarded by Novartis Research Foundation

Awarded by Ontario Ministry of Economic Development and Innovation

Awarded by Pfizer

Awarded by Takeda

Awarded by Wellcome Trust

Funding Acknowledgements

We wish to thank N. Nicola for helpful comments and discussion, P. Rueda and C. Quillici for technical assistance, Tracy Wilson for generating the wild-type and SH2-mutant CIS expression plasmids, R. Anderson for the E0771.LMB cells, and L. Town, K. Elder, T. Camilleri and J. Sutton for excellent animal husbandry. We are grateful to the staff of the WEHI Bioservices, Monoclonal antibody facility, Flow cytometry facility and Clinical Translational Centre. This work is supported by program and project grants from the National Health and Medical Research Council (NHMRC) of Australia (1027472 to S.C., N.D.H. and G.T.B., 1013667 and 1098960 to M.J.S., 1047903 to G.T.B., 1016647 to J.G.Z., S.E.N. and W.S.A., 1049407, 1066770 and 1057852 to N.D.H., and 1078763 to D.H.D.G.), as well as an NHMRC Independent Research Institute Infrastructure Support scheme grant and a Victorian State Government Operational Infrastructure Scheme grant. N.D.H. is a recipient of a Melanoma Research Grant from the Harry J Lloyd Charitable Trust and R.B.D. is supported by a Leukemia Foundation scholarship. This work was also supported by fellowships from the NHMRC (GNT0461276 to N.D.H., 1058344 to W.S.A., 545952 to D.S.H., 1090236 to D.H.D.G., 1089072 to C. T., Australia Fellowship 1078671 to M.J.S.), the Australian Research Council (G.T.B.) and the Menzies Foundation (N.D.H.). E.M.P. is supported by a Schroedinger Fellowship from the Austrian Science Fund (FWF): J-3635. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer PHARMA AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust [092809/Z/10/Z].