Receptor Activator for NF- B Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance

Department of Hematology and Oncology, Eberhard Karls University, 72076 Tuebingen, Germany
The Journal of Immunology (Impact Factor: 4.92). 12/2012; 190(2). DOI: 10.4049/jimmunol.1201792
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute and chronic myeloid leukemia (AML, CML) are hematologic malignancies arising from oncogene-transformed hematopoietic stem/progenitor cells known as leukemia stem cells (LSCs). LSCs are selectively resistant to various forms of therapy including irradiation or cytotoxic drugs. The introduction of tyrosine kinase inhibitors has dramatically improved disease outcome in patients with CML. For AML, however, prognosis is still quite dismal. Standard treatments have been established more than 20 years ago with only limited advances ever since. Durable remission is achieved in less than 30% of patients. Minimal residual disease (MRD), reflected by the persistence of LSCs below the detection limit by conventional methods, causes a high rate of disease relapses. Therefore, the ultimate goal in the treatment of myeloid leukemia must be the eradication of LSCs. Active immunotherapy, aiming at the generation of leukemia-specific cytotoxic T cells (CTLs), may represent a powerful approach to target LSCs in the MRD situation. To fully activate CTLs, leukemia antigens have to be successfully captured, processed, and presented by mature dendritic cells (DCs). Myeloid progenitors are a prominent source of DCs under homeostatic conditions, and it is now well established that LSCs and leukemic blasts can give rise to "malignant" DCs. These leukemia-derived DCs can express leukemia antigens and may either induce anti-leukemic T cell responses or favor tolerance to the leukemia, depending on co-stimulatory or -inhibitory molecules and cytokines. This review will concentrate on the role of DCs in myeloid leukemia immunotherapy with a special focus on their generation, application, and function and how they could be improved in order to generate highly effective and specific anti-leukemic CTL responses. In addition, we discuss how DC-based immunotherapy may be successfully integrated into current treatment strategies to promote remission and potentially cure myeloid leukemias.
    Full-text · Article · Dec 2013 · Frontiers in Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Receptor activator of NFκB ligand (RANKL) is mainly known for its role in bone metabolism, constituting a target for therapeutic interventions. Increasing evidence suggests that RANKL is also involved in oncogenesis and tumor progression, including a prominent role in host-tumor interaction. Our data suggest that targeting RANKL may reinforce natural killer (NK) cell-mediated antitumor responses in patients affected by hematological malignancies.
    Full-text · Article · May 2013 · OncoImmunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute myeloid leukemia (AML) cells are killed by allogeneic NK cells. However, autologous NK cells from AML patients express decreased levels of activating receptors, and show reduced cytotoxicity. Here, we investigated how interactions between NK and AML cells might cause loss of NK cell activity in patients. Our results show that AML cell lines and primary blasts alter the NK cell phenotype, reducing their cytotoxic potential upon prolonged contact. Down-regulation of NK-cell-activating receptors was contact-dependent and correlated with conjugate formation. Time-lapse imaging of HL60 AML cell line and NK-cell interactions showed a high proportion of non-cytolytic contacts. Studies of NK-cell immunological synapses revealed a defect in lytic synapse formation. Namely, despite correct F-actin and LFA-1 recruitment, polarization of lytic granules toward primary blasts or AML cell lines was reduced. The NK-AML cell line synapses showed impairment of CD3ζ recruitment. Attempts to correct these synapse defects by cytokine stimulation of NK cells improved conjugate formation, but not granule polarization. Pre-treatment of AML cell lines with the immuno-modulating molecule lenalidomide significantly enhanced granule polarization. We speculate that combining immunomodulatory drugs and cytokines could increase AML cell sensitivity to autologous NK cells and reinforce the activity of allogeneic NK cells in adoptive immunotherapy.This article is protected by copyright. All rights reserved
    Full-text · Article · Oct 2014 · European Journal of Immunology