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

Détails

ID Serval
serval:BIB_C841B0E9495C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.
Périodique
Journal of Immunology
Auteur(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
Statut éditorial
Publié
Date de publication
2013
Volume
190
Numéro
2
Pages
821-831
Langue
anglais
Résumé
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.
Mots-clé
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
Création de la notice
07/02/2013 9:43
Dernière modification de la notice
03/03/2018 21:21
Données d'usage