Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 43, Issue 1, Pages 249-257Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201242735
Keywords
IFN-gamma; Immunotherapy; Monocytes; Natural killer cells; Zoledronic acid
Categories
Funding
- Swedish Research Council
- Swedish Cancer Society
- European Research Council Society
- Karolinska Institutet
- Jeanssons Stiftelser
- Ake Wibergs Stiftelse
- Magnus Bergvalls Stiftelse
- Fredrik och Ingrid Thurings Stiftelse
- Stiftelsen Clas Groschinskys Minnesfond
- Swedish Society of Medicine
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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 ?d 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-?; when cultured in the presence of neutralizing antibodies to IFN-?, 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.
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