title: Receptor activator for NF-κB ligand in acute myeloid leukemia: expression, function, and modulation of NK cell immunosurveillance.
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.
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls University, 72076 Tuebingen, Germany.
authors.forename: Benjamin Joachim
authors.initials: BJ
authors.lastname: Schmiedel
authors.forename: Tina
authors.initials: T
authors.lastname: Nuebling
authors.forename: Julia
authors.initials: J
authors.lastname: Steinbacher
authors.forename: Alexandra
authors.initials: A
authors.lastname: Malinovska
authors.forename: Constantin Maximilian
authors.initials: CM
authors.lastname: Wende
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Ludger
authors.initials: L
authors.lastname: Grosse-Hovest
authors.forename: Helmut Rainer
authors.initials: HR
authors.lastname: Salih
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D002460:Cell Line; D000069448:Denosumab; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D000069448:Denosumab