title: Reactive oxygen species- and DNA damage response-dependent NK cell activating ligand upregulation occurs at transcriptional levels and requires the transcriptional factor E2F1.
abstract: Increasing evidence indicates that cancer cell stress induced by chemotherapeutic agents promote antitumor immune responses and contribute to their full clinical efficacy. In this article, we identify the signaling events underlying chemotherapy-induced NKG2D and DNAM-1 ligand expression on multiple myeloma (MM) cells. Our findings indicate that sublethal doses of doxorubicin and melphalan initiate a DNA damage response (DDR) controlling ligand upregulation on MM cell lines and patient-derived malignant plasma cells in Chk1/2-dependent and p53-independent manner. Drug-induced MICA and PVR gene expression are transcriptionally regulated and involve DDR-dependent E2F1 transcription factor activity. We also describe the involvement of changes in the redox state in the control of DDR-dependent upregulation of ligand surface expression and gene transcriptional activity by using the antioxidant agent N-acetyl-L-cysteine. Finally, in accordance with much evidence indicating that DDR and oxidative stress are major determinants of cellular senescence, we found that redox-dependent DDR activation upon chemotherapeutic treatment is critical for MM cell entry in premature senescence and is required for the preferential ligand upregulation on senescent cells, which are preferentially killed by NK cells and trigger potent IFN-γ production. We propose immunogenic senescence as a mechanism that promotes the clearance of drug-treated tumor cells by innate effector lymphocytes, including NK cells.
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy; alessandra.soriani@uniroma1.it angela.santoni@uniroma1.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy;
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Iannitto
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy;
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Ricci
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy;
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fionda
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy;
authors.forename: Giulia
authors.initials: G
authors.lastname: Malgarini
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Morrone
authors.affiliation: Center for Life Nano Science-Italian Institute of Technology Sapienza, 00161 Rome, Italy; and.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Peruzzi
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Cippitelli
authors.affiliation: Department of Molecular Medicine, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy; alessandra.soriani@uniroma1.it angela.santoni@uniroma1.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D000098862:T Lineage-Specific Activation Antigen 1; D050687:E2F1 Transcription Factor; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017382:Reactive Oxygen Species; D011991:Receptors, Virus; C066100:poliovirus receptor; D004317:Doxorubicin; D008558:Melphalan