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

Dhifaf Sarhan, Padraig D'Arcy, Erik Wennerberg, Majken Lidén, Jin Hu, Ola Winqvist, Charlotte Rolny, Andreas Lundqvist

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)249-257
Number of pages9
JournalEuropean Journal of Immunology
Volume43
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • IFN-γ
  • Immunotherapy
  • Monocytes
  • Natural killer cells
  • Zoledronic acid

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