Editors' ChoiceImmunology

Turning on NK cells

Sci. Signal.  28 Jun 2016:
Vol. 9, Issue 434, pp. ec150
DOI: 10.1126/scisignal.aah4264

Many anticancer immunotherapies include immune checkpoint inhibitors, reagents that block suppressive signaling in cytotoxic T lymphocytes (CTLs), thus enabling these cells to mount an effective immune response and kill tumor cells. Natural killer (NK) cells, which are activated by stimulatory receptors and the cytokine interleukin-15 (IL-15), also perform immunosurveillance and killing of tumor cells, which led Delconte et al. to investigate whether similar checkpoints acted to suppress NK cell antitumor activity. Stimulation of NK cells with IL-15 in vitro led to the increased abundance of cytokine-inducible Src homology 2 (SH2)–containing protein (CIS), a member of the suppressor of cytokine signaling (SOCS) family of proteins. In NK cells in which Cish (which encodes CIS) was knocked down, IL-15 induced increased proliferation compared to that in control NK cells, as well as enhanced production of the inflammatory cytokine interferon-γ (IFN-γ) and killing of tumor cells. Loss of CIS in NK cells led to increased Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) signaling in response to IL-15. In wild-type NK cells, CIS bound directly to JAK1 and promoted its proteasomal degradation. In addition, the binding of CIS to JAK1 inhibited its kinase activity. Compared with wild-type mice, Cish–/– mice had fewer metastases when injected with various tumor cell lines. Antibody-mediated depletion of NK cells from the Cish–/– mice made them more susceptible to metastasis. Last, in both experimental and spontaneous mouse models of breast cancer metastasis, Cish–/– mice had reduced tumor burden compared with that of wild-type mice. Together, these data suggest that CIS acts as an intracellular NK cell checkpoint. As Zitvogel and Kroemer discuss, further studies should address how the CIS-JAK1 interaction can be targeted to unleash the full antitumor activity of NK cells.

R. B. Delconte, T. B. Kolesnik, L. F. Dagley, J. Rautela, W. Shi, E. M. Putz, K. Stannard, J.-G. Zhang, C. Teh, M. Firth, T. Ushiki, C. E. Andoniou, M. A. Degli-Esposti, P. P. Sharp, C. E. Sanvitale, G. Infusini, N. P. D. Liau, E. M. Linossi, C. J. Burns, S. Carotta, D. H. D. Gray, C. Seillet, D. S. Hutchinson, G. T. Belz, A. I. Webb, W. S. Alexander, S. S. Li, A. N. Bullock, J. J. Babon, M. J. Smyth, S. E. Nicholson, N. D. Huntington, CIS is a potent checkpoint in NK cell–mediated tumor immunity. Nat. Immunol. 17, 816–824 (2016). [PubMed]

L. Zitvogel, G. Kroemer, Unchaining NK cell–mediated anticancer immunosurveillance. Nat. Immunol. 17, 746–747 (2016). [PubMed]

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