Effector Gammadelta T Cells and Tumor Cells as Immune Targets of Zoledronic Acid in Multiple Myeloma

Leukemia. 2005 Apr;19(4):664-70. doi: 10.1038/sj.leu.2403693.

Abstract

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood Vgamma9/Vdelta2 (gammadelta) T cells of normal donors and multiple myeloma (MM) patients. gammadelta 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 gammadelta T cells was observed in 100% of normal donors and 50% of MM patients. gammadelta 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 gammadelta 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 gammadelta T cells and by enhancing the immunosensitivity of myeloma cells to gammadelta T cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Communication / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Cells, Cultured
  • Diphosphonates / pharmacology*
  • Humans
  • Imidazoles / pharmacology*
  • Immunologic Factors / immunology
  • Immunologic Memory
  • In Vitro Techniques
  • Interleukin-2 / pharmacology
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • Zoledronic Acid

Substances

  • Antineoplastic Agents
  • Diphosphonates
  • Imidazoles
  • Immunologic Factors
  • Interleukin-2
  • Receptors, Antigen, T-Cell, gamma-delta
  • Zoledronic Acid