title: Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ.
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.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dhifaf
authors.initials: D
authors.lastname: Sarhan
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.forename: Majken
authors.initials: M
authors.lastname: Lidén
authors.forename: Jin
authors.initials: J
authors.lastname: Hu
authors.forename: Ola
authors.initials: O
authors.lastname: Winqvist
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D007376:Interleukin-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077211:Zoledronic Acid; D007371:Interferon-gamma