Effector γδ T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood V gamma 9/V delta 2 (gamma delta) T cells of normal donors and multiple myeloma (MM) patients. gamma delta T cells were stimulated with Zol and low doses of interleukin- 2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of gamma delta T cells was observed in 100% of normal donors and 50% of MM patients. gamma delta T cells produced IFN-gamma, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM gamma delta T cells that proliferated in response to Zol ( responders), whereas effector cells were predominant in those that did not ( nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of gamma delta T cells and by enhancing the immunosensitivity of myeloma cells to gamma delta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.