TAM Receptor or CBL-B Inhibition Enables Tumor Rejection by NK Cells

Loss of the E3 ubiquitin ligase CBL-B improves tumor surveillance by the immune system, but the underlying mechanisms are not completely understood. Paolino and colleagues investigated the contribution of the innate immune system, particularly natural killer (NK) cells, toward tumor rejection in CBL-B–deficient mice and found that loss of CBL-B in NK cells improved NK cell proliferative and cytotoxic responses toward target cells in vitro, indicating that CBL-B negatively regulates NK cell activity and raising the possibility that CBL-B–deficient NK cells may promote tumor rejection. Indeed, the growth and metastasis of melanoma cells implanted into CBL-B–deficient mice or into mice expressing an E3 ligase-defective CBL-B were suppressed in an NK cell–dependent manner. In addition, transfer of CBL-B–deficient or CBL-B–disabled NK cells into syngeneic hosts reduced metastasis in multiple tumor models. To determine how CBL-B regulates NK cell activity, the authors performed in vitro ubiquitylation reactions on 9,000 proteins and identified the TYRO3, AXL, and MER (TAM) receptor tyrosine kinases as targets of CBL-B. Exposure to the TAM ligand GAS6 impaired activation of wild-type NK cells, whereas loss of CBL-B reduced TAM receptor ubiquitylation, decreased GAS6-induced TAM receptor internalization, and rendered NK cells resistant to GAS6-mediated inactivation. Administration of a small-molecule TAM receptor kinase inhibitor blocked GAS6 inhibition of wild-type NK cell activity in vitro and reduced metastases in several tumor models when administered intraperitoneally or orally. Interestingly, low doses of warfarin, which blocks stimulation of TAM receptors without affecting coagulation, also enhanced NK cell cytotoxicity and reduced metastases in wild-type mice injected with melanoma cells. Together, these data implicate CBL-B and TAM as negative regulators of NK cell activity and suggest that interfering with this pathway may improve NK cell–mediated tumor surveillance.

Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014 Feb 19 [Epub ahead of print].

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