Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.

Details

Serval ID
serval:BIB_C841B0E9495C
Type
Article: article from journal or magazin.
Collection
Publications
Title
Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.
Journal
Journal of Immunology
Author(s)
Schmiedel B.J., Nuebling T., Steinbacher J., Malinovska A., Wende C.M., Azuma M., Schneider P., Grosse-Hovest L., Salih H.R.
ISSN
1550-6606 (Electronic)
ISSN-L
0022-1767
Publication state
Published
Issued date
2013
Volume
190
Number
2
Pages
821-831
Language
english
Abstract
The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK-RANKL interaction in NK cell-mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK-RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.
Keywords
Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized/pharmacology, Cell Line, Female, Gene Expression Regulation, Leukemic, Humans, Immunomodulation/drug effects, Killer Cells, Natural/immunology, Killer Cells, Natural/metabolism, Leukemia, Myeloid, Acute/genetics, Leukemia, Myeloid, Acute/immunology, Male, Middle Aged, Protein Binding, RANK Ligand/antagonists & inhibitors, RANK Ligand/genetics, Receptor Activator of Nuclear Factor-kappa B/genetics, Receptor Activator of Nuclear Factor-kappa B/metabolism, Signal Transduction/drug effects, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
07/02/2013 9:43
Last modification date
09/05/2019 1:08
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