Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ

Eur J Immunol. 2013 Jan;43(1):249-57. doi: 10.1002/eji.201242735. Epub 2012 Oct 26.


Natural killer (NK) cells are innate lymphocytes that are able to directly kill tumor cells through different mechanisms including ligation of TNF-related apoptosis-inducing ligand (TRAIL) receptors. Zoledronic acid (ZA) is a bisphosphonate known to upregulate the expression of TRAIL on human γδ T cells. Here, we investigated whether exposure to ZA would upregulate TRAIL expression on human NK cells and augment their cytotoxicity against tumor cells. When cocultured with monocytes, treatment with ZA and IL-2 resulted in a significant upregulation of TRAIL expression on human NK cells (p = 0.002). Consequently, ZA-primed NK cells were significantly more cytotoxic against TRAIL sensitive tumor cells (p < 0.0001). In the presence of ZA and IL-2, monocytes produced high levels of IFN-γ; when cultured in the presence of neutralizing antibodies to IFN-γ, TRAIL expression and TRAIL-mediated cytotoxicity of NK cells were significantly reduced. Furthermore, in tumor-bearing SCID/Beige mice, a significant delayed tumor progression and prolonged survival was observed after infusion of ZA-primed NK cells compared with that observed in mice infused with unprimed NK cells. These findings represent a novel approach to potentiate TRAIL-mediated apoptosis by adoptively infused NK cells that could improve the outcome in patients with cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Cytotoxicity, Immunologic*
  • Diphosphonates / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Humans
  • Imidazoles / pharmacology
  • Interferon-gamma / metabolism*
  • Interleukin-2 / pharmacology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / transplantation
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, SCID
  • Monocytes / immunology*
  • Neoplasms / immunology
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Xenograft Model Antitumor Assays
  • Zoledronic Acid


  • Diphosphonates
  • Imidazoles
  • Interleukin-2
  • TNF-Related Apoptosis-Inducing Ligand
  • Zoledronic Acid
  • Interferon-gamma