Inactivation of E3 Ubiquitin Ligase Cbl-b Allows Natural Killer Cells to Control Metastases

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New therapeutic approaches to blocking inhibitory pathways of the immune system have raised hopes that such treatments might thwart development of metastases. In a study in Nature, Paolino and colleagues have shown that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity permits natural killer cells to spontaneously reject metastatic tumors.

After TAM tyrosine kinase receptors (Tyro3, Axl, and Mer) were identified as ubiquitylation substrates for Cbl-b, treatment of wild-type NK cells with a novel small-molecule TAM kinase inhibitor was shown to dramatically increase their antimetastatic activity in vivo. In mouse models, oral or intraperitoneal administration of the TAM inhibitor reduced the development of murine mammary cancer and melanoma metastases in a natural killer cell–dependent manner.

The investigators also found that the anticoagulant warfarin exerts antimetastatic activity in mice via Cbl-b/TAM receptors in natural killer cells, providing a molecular mechanism for the reported antitumor and antimetastatic effects of warfarin and other anticoagulants.

The investigators concluded, “This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a ‘pill’ that awakens the innate immune system to kill cancer metastases.” ■

Paolino M, et al: Nature 507:508-512, 2014.




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