Low-dose bortezomib increases the expression of NKG2D and DNAM-1 ligands and enhances induced NK and γδ T cell-mediated lysis in multiple myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy, although bortezomib has markedly improved its outcomes. Growing clinical evidence indicates that enhancing induced natural killer (NK) or gamma delta T cells for infusion is useful in the treatment of MM. However, whether combination treatment with bortezomib and induced NK and gamma delta T cells further improves outcomes in MM, and how the treatments should be combined, remain unclear. Herein, we found that low-dose bortezomib did not suppress the viability of induced NK and gamma delta T cells, but did induce MM cell apoptosis. Importantly, low-dose bortezomib increased the expression of NKG2D and DNAM-1 ligands on MM cells, which sensitized the multiple myeloma cells to lysis by induced NK and gamma delta T cells. Our results suggested that combination treatment with low-dose bortezomib and induced NK or gamma delta T cells had a synergistic cytotoxic effect on MM cells. This study provided a proof of principle for the design of future trials and investigation of this combination therapeutic strategy for MM treatment.