Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma

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Abstract
Bisphosphonates are well-known inhibitors of osteoclastic bone resorption, but recent clinical reports support the possibility of direct or indirect antitumor effects by these compounds. Because bisphosphonates share structural homologies with recently identified γδ T-cell ligands, we examined the stimulatory capacity of bisphosphonates to γδ T cells and determined whether γδ T-cell stimulation by bisphosphonates could be exploited to generate antiplasma cell activity in multiple myeloma (MM). All tested aminobisphosphonates (alendronate, ibandronate, and pamidronate) induced significant expansion of γδ T cells (Vγ9Vδ2 subset) in peripheral blood mononuclear cell cultures of healthy donors at clinically relevant concentrations (half-maximal activity, 0.9-4 μmol/L). The proliferative response of γδ T cells to aminobisphosphonates was IL-2 dependent, whereas activation of γδ T cells (up-regulation of CD25 and CD69) occurred in the absence of exogenous cytokines. Pamidronate-activated γδ T cells produced cytokines (ie, interferon [IFN]-γ) and exhibited specific cytotoxicity against lymphoma (Daudi) and myeloma cell lines (RPMI 8226, U266). Pamidronate-treated bone marrow (BM) cultures of 24 patients with MM showed significantly reduced plasma cell survival compared with untreated cultures, especially in cultures in which activation of BM-γδ T cells was evident (14 of 24 patients with MM). γδ T-cell depletion from BM cultures completely abrogated the cytoreductive effect on myeloma cells in 2 of 3 tested patients with MM. These results show that aminobisphosphonates stimulating γδ T cells have pronounced effects on the immune system, which might contribute to the antitumor effects of these drugs.