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

Abstract

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vc9/Vd2 (cd) T cells of normal donors and multiple myeloma (MM) patients. cd 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 cd T cells was observed in 100% of normal donors and 50% of MM patients. cd T cells produced IFN-c, 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 cd 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 cd T cells and by enhancing the immunosensitivity of myeloma cells to cd T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

“…Bisphosphonates also have antiangiogenesis properties (8,9) and can activate ␥␦ T cells (10,11). The use of bisphosphonates in patients with multiple myeloma and metastatic cancer to the bones, such as breast, prostate, lung, and renal cell carcinomas, has resulted in a statistically significant reduction in skeletal complications, including pathologic fractures, spinal cord compression, hypercalcemia of malignant disease, and the need for subsequent radiotherapy or surgery to bone (12)(13)(14).…”

Activation of cytotoxic T-cell receptor T lymphocytes in response to specific stimulation in myelodysplastic syndromes

“…Similar findings were reported in multiple myeloma patients following stimulation with zoledronic acid+IL-2. 16 In cultures from MDS patients, the response to BrHPP was independent of the γδ T-cell repertoire, and IL-15 did not increase the expansion of effector memory T cells, suggesting that the altered expansion we found in some patients was due to an intrinsic defect of those cells.…”

“…10 This cell population has lytic potential against various tumor cell lines in vitro [11][12][13] and could play a role in clinical responses in lymphoid malignancies including lymphoma and multiple myeloma. [14][15][16] In addition, γδ T cells are potent and rapid producers of interferon-γ and tumor necrosis factor-α, 17 and potentially act as antigen-presenting cells. 18 They have a regulatory function, interact with myeloid cells and are induced in various forms of tolerance.…”

Zoledronic acid negatively affects the expansion of in vitro activated human NK cells and their cytolytic interactions with Ewing sarcoma cells

“…At clinically relevant concentrations, these agents were found to induce specific activation and IL-2-dependent proliferation of a peripheral blood lymphocyte subset, γδ T cells (20). Moreover, ZA can inhibit the activation of monocyte-derived dendritic cells (21).…”