The function of natural killer (NK) cells is regulated by inhibitory and activating signals delivered by cell surface receptors, 1-7F9 is a fully human monoclonal antibody (mAb) directed against KIR2DL1 and KIR2DL2/3 receptors that block its interaction with its HLA-C ligands breaking NK cell tolerance to autologous tumor cells. Lenalidomide has been shown to increase NK cell cytotoxicity in vitro. The combination of lenalidomide and 1-7F9 enhanced NK cell mediated cytotoxicity against U266 cells beyond that observed with each agent alone. Lenalidomide also increased the expression of NKG2D, DNAM-I and TRAIL ligands including: MICA, ULB P2, CD1 12 and DR 4 on U266 cells. In in vitro cytotoxicity assays, lenalidomide enhanced the susceptibility of myeloma cell lines to NK cell. The NK cell signaling pathways was also explored after lenalidomide treatment and the results show that lenalidomide may upregulate the phospho-SHIP1 (Tyr1020) and has no effect on phosphop44/42 (ERK 1/2) (Thr202/Tyr204) in NK cells. These results provide pre-clinical rationale for clinical investigation of 1-7F9 anti-KIR mAb and lenalidomide in MM.
