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Immunosurveillance Function, and Modulation of NK Cell Acute Receptor Activator for NF-κB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance This information is current as of September 27, 2021. Benjamin Joachim Schmiedel, Tina Nuebling, Julia Steinbacher, Alexandra Malinovska, Constantin Maximilian Wende, Miyuki Azuma, Pascal Schneider, Ludger Grosse-Hovest and Helmut Rainer Salih J Immunol 2013; 190:821-831; Prepublished online 14 Downloaded from December 2012; doi: 10.4049/jimmunol.1201792 http://www.jimmunol.org/content/190/2/821 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/12/14/jimmunol.120179 Material 2.DC1 References This article cites 49 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/190/2/821.full#ref-list-1 by guest on September 27, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Receptor Activator for NF-kB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance Benjamin Joachim Schmiedel,* Tina Nuebling,* Julia Steinbacher,* Alexandra Malinovska,* Constantin Maximilian Wende,* Miyuki Azuma,† Pascal Schneider,‡ Ludger Grosse-Hovest,x and Helmut Rainer Salih* The TNF family member receptor activator for NF-kB 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 Downloaded from 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 http://www.jimmunol.org/ with a more pronounced effect on IFN-g 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 neutral- ization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients. The Journal of Immu- nology, 2013, 190: 821–831. atural killer cells are cytotoxic lymphocytes that play controlling leukemia in an autologous setting. This is also sup- an important role in anti-tumor immunity (1). Their in- ported by the observation that NK cell counts and activity are N volvement in immunosurveillance of hematopoietic ma- reduced in patients with leukemia and that activity levels of au- by guest on September 27, 2021 lignancies and in particular acute myeloid leukemia (AML) is tologous NK cells are associated with survival of leukemia patients highlighted by studies on haploidentical stem cell transplantation (7–9). Because NK cell reactivity is governed by a balance of mul- \(SCT), where the recipient’s leukemia cells fail to inhibit donor tiple inhibitory and activating receptors, interaction of NK cells NK cells via killer Ig-like receptors (KIRs), and KIR disparity is and leukemia cells is dependent on various immunoregulatory mol- associated with powerful graft versus leukemia effects and better ecules far beyond HLA class I–specific inhibitory KIR receptors clinical outcome (2–4). The observation that leukemia cells may (10, 11). Among others, many members of the TNF/TNFR family downregulate HLA class I molecules (5, 6), presumably to escape influence NK cell activation, and several TNF/TNFR family adaptive immunity, suggests that NK cells are also involved in members have been found to be expressed on AML cells and in- fluence anti-leukemia reactivity of NK cells that express their *Department of Hematology and Oncology, Eberhard Karls University, 72076 Tue- respective counterpart (12–14). bingen, Germany; †Department of Molecular Immunology, Tokyo Medical and Den- The TNFR family member receptor activator for NF-kB (RANK; tal University, Tokyo 133-8510, Japan; ‡Department of Biochemistry, University of x TNFRSF11A) and its ligand (receptor activator for NF-kB ligand; Lausanne, Epalinges, CH-1066 Switzerland; and Department of Immunology, Eber- hard Karls University, 72076 Tuebingen, Germany RANKL) are mainly known for their key role in regulating bone Received for publication June 28, 2012. Accepted for publication November 9, 2012. metabolism (15, 16) but were also found to influence the inter- This work was supported by grants from Deutsche Forschungsgemeinschaft action of dendritic cells (DCs) and T cells as well as the path- (SA1360/7-1, SFB685 TP A7), Wilhelm Sander-Stiftung (2007.115.3), and Deutsche ophysiology of hematopoietic malignancies and metastasis of solid Krebshilfe (109620). P.S. is supported by grants from the Swiss National Science tumors (17–25). Notably, available data indicate that RANK is Foundation. also expressed on NK cells (26), but to date nothing is known Address correspondence and reprint requests to Prof. Helmut Rainer Salih, Depart- ment of Hematology and Oncology, Eberhard Karls University, Otfried-Mueller regarding the functional relevance of RANK–RANKL interaction Strasse 10, 72076 Tuebingen, Germany. E-mail address: [email protected] for NK cell reactivity. We report in this study that AML cells tuebingen.de express RANKL in a high proportion of cases and that NK cells The online version of this article contains supplemental material. of AML patients display upregulated expression of its counterpart Abbreviations used in this article: AML, acute myeloid leukemia; CLL, chronic RANK. To account for the fact that several TNF/TNFR family lymphoid leukemia; DC, dendritic cell; FAB, French–American–British classifica- tion; KIR, killer Ig-like receptor; mRANKL, membrane-bound RANKL; RANK, members may mediate different effects in mice and men (14, 27, receptor activator for NF-kB; RANKL, receptor activator for NF-kB ligand; SCT, 28), we set out to study the role of RANKL in AML pathophys- stem cell transplantation; SFI, specific fluorescence index; sRANKL, soluble iology by using primary malignant cells of leukemia patients and RANKL. examined the functional relevance of RANK–RANKL interaction Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 for NK cell immunosurveillance by using PBMCs of healthy www.jimmunol.org/cgi/doi/10.4049/jimmunol.1201792 822 RANKL IMPAIRS NK CELL REACTIVITY donors as effector cells thereby mimicking the situation in patients instructions. Absorbance was measured at 450 nm with 650 nm as refer- that undergo allogeneic SCT. ence wavelength, and results are shown as means of triplicate measure- ments. Materials and Methods NK cell activation, degranulation, cytotoxicity, and cytokine Patients production PBMCs of AML patients obtained at the time of diagnosis before therapy Upregulation of CD69 and CD107a as markers for NK activation and de- and of healthy donors were isolated by density gradient centrifugation after granulation, respectively, was analyzed by FACS. NK cells within PBMCs obtaining informed consent in accordance with the Helsinki protocol. In were selected by staining for CD56+CD32. Cytotoxicity was analyzed by . functional analyses, PBMCs of patients with 80% blast count according 2 h BATDA europium release assays as previously described (13). IFN-g to differential blood count in blood smears were used without further production was analyzed using the ELISA mAb set from Thermo Scientific purification to avoid potential artifacts by Ab-based isolation techni- (Rockford, IL) according to the manufacturer’s instructions. Lysis rates and ques. The study was performed according to the guidelines of the local cytokine concentrations in supernatants are shown as means of triplicate ethics committee. measurements in each experiment. Transfectants and cell lines The RANKL-transfectants (L-RANKL) as well as parental controls (L Results cells) were previously described (29). The human AML cell line HL-60 Expression of RANKL in AML was obtained internally at Eberhard Karls University Tuebingen. Au- thenticity was determined
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