title: Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis.
abstract: Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies.
authors.affiliation: 1] Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wild
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: B J
authors.initials: BJ
authors.lastname: Schmiedel
authors.affiliation: Interfaculty Institute of Biochemistry, Eberhard Karls University, Tuebingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Maurer
authors.affiliation: 1] Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Raab
authors.affiliation: Department of Immunology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Prokop
authors.affiliation: Department of Immunology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: 1] Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Dörfel
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Schneider
authors.affiliation: 1] Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany [2] Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H R
authors.initials: HR
authors.lastname: Salih
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D010446:Peptide Fragments / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D053264:B-Cell Activating Factor; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D000069283:Rituximab; C511911:belimumab