Editors' ChoiceCancer Immunotherapy

Natural Killer Cells on the Attack

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Sci. Signal.  01 Apr 2014:
Vol. 7, Issue 319, pp. ec84
DOI: 10.1126/scisignal.2005320

A promising avenue for cancer treatment is leveraging the body’s own immune system to target the cancer cells. Paolino et al. showed that in multiple cancer models, tumor growth and metastasis was reduced in mice lacking Cbl-b, an E3 ubiquitin ligase that targets surface receptors, or in Cbl-b–deficient mice reconstituted with a catalytically inactive mutant. This antitumor activity was abolished if the mice were depleted of natural killer (NK) cells, a cytotoxic cell type of the innate immune system. In vitro ubiquitylation reactions with more than 9000 human proteins identified TYRO3, a member of the receptor tyrosine kinase TAM (Tyro, Axl, Mer) family, as the top candidate substrate of CBL-B. In response to the TAM ligand Gas6, activated mouse NK cells, but not those lacking Cbl-b activity, exhibited decreased proliferation and interferon-γ production and reduced amounts of all three TAM family receptors from the cell surface. The authors developed LDC1267 to selectively inhibit the kinase activity of TAMs and showed that LDC1267 prevented the Gas6-mediated inhibition of activated NK cells without affecting NK cells deficient in Cbl-b function. The antitumor response was increased by adoptive transfer of LDC1267-treated NK cells to a similar extent as that of adoptively transferred Cbl-b–deficient NK cells, indicating that NK cells were the relevant target of the drug. LCD1267 promoted an NK cell–dependent antitumor response when delivered intraperitoneally or orally into mice with different types of cancer. Finally, the anticoagulant warfarin has a tumor-reducing effect in rodent cancer models and inhibits TAM activity. Treatment of mice with a dose of warfarin too low to affect coagulation enhanced NK cell cytotoxicity and reduced melanoma metastasis in a manner dependent on NK cells. Thus, this strategy of inhibiting TAMs may be an effective therapeutic option in cancer, and warfarin may potentially be repurposed for this clinical application.

M. Paolino, A. Choidas, S. Wallner, B. Pranjic, I. Uribesalgo, S. Loeser, A. M. Jamieson, W. Y. Langdon, F. Ikeda, J. P. Fededa, S. J. Cronin, R. Nitsch, C. Schultz-Fademrecht, J. Eickhoff, S. Menninger, A. Unger, R. Torka, T. Gruber, R. Hinterleitner, G. Baier, D. Wolf, A. Ullrich, B. M. Klebl, J. M. Penninger, The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014). [PubMed]