The immunomodulatory drugs (IMiDs) have been used for the treatment of multiple myeloma and additional pharmacological effects have been recognized including anti-angiogeneic and immunoregulatory effect. To exert the immunoregulatory effect of IMiDs, NK cell has been known as one of the effector cells, however, the mechanism by which IMiDs show anti-tumor effect through NK cells remains unclear. In this study, we examined the role of NK cells in the anti-metastatic effect of IMiDs and its mechanism of action by focusing on in vivo NK cell homeostasis and maturation processes.
B16F10-Luc2 cells stably expressing firefly luciferase gene, were i.v. inoculated and the lung micro-metastasis was quantified by using bioluminescence imaging system (IVIS Lumina). The systemic Thalidomide treatment strongly suppressed B16F10 melanoma lung metastases. By depleting NK cells with anti-asialo GM1 Ab, we demonstrated the critical requirement of NK cells for the anti-metastatic effect of Thalidomide. Further, we have found that IFN- g production from NK cell greatly contributed to lung metastases restraint of Thalidomide by the experiment with IFN- g KO B6 mouse. In align with the NK cell-dependent anti-metastatic effect, the proportion of terminally differentiated CD27lo NK cell subset were increased in the peripheral tissues of Thalidomide-treated mice. In addition to the increase of CD27lo mature NK cells, we also observed the dynamic change in the expression of transcription factors that are known to regulate NK cell differentiation and maturation upon Thalidomide treatment in vivo. Collectively, our results indicate that IMiDs may mediate its anti-metastatic effect through modulating in vivo NK cell homeostasis and maturation.