title: Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells.
abstract: Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses.
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy; alessandra.zingoni@uniroma1.it angela.santoni@uniroma1.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Cecere
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vulpis
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fionda
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Rosa
authors.initials: R
authors.lastname: Molfetta
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.affiliation: Department of Cellular Biotechnology and Hematology, "Sapienza" University of Rome, 00161 Rome, Italy;
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Department of Cellular Biotechnology and Hematology, "Sapienza" University of Rome, 00161 Rome, Italy;
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Institute for Clinical Transfusion Medicine and Immunogenetics Ulm of the German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, 89081 Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, 89081 Ulm, Germany; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fuerst
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Amendola
authors.affiliation: Institute for Clinical Transfusion Medicine and Immunogenetics Ulm of the German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, 89081 Ulm, Germany; Institute of Transfusion Medicine, University of Ulm, 89081 Ulm, Germany; and.
authors.forename: Joannis
authors.initials: J
authors.lastname: Mytilineos
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerboni
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Rossella
authors.initials: R
authors.lastname: Paolini
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Cippitelli
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, Rome 00161, Italy; Institute Pasteur-Fondazione Cenci Bolognetti, "Sapienza" University of Rome, 00161 Rome, Italy alessandra.zingoni@uniroma1.it angela.santoni@uniroma1.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology*; D000072197:ADAM10 Protein; D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000276:immunology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D003603:Cytotoxins / Q000494:pharmacology*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction; D053668:Syndecan-1 / Q000235:genetics / Q000276:immunology
chemical_list: D003603:Cytotoxins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017382:Reactive Oxygen Species; C508241:SDC1 protein, human; D053668:Syndecan-1; D004317:Doxorubicin; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D008558:Melphalan