Expression of ligands for NK cell receptors NKG2D and DNAM-1 on drug-induced senescent Multiple Myeloma cells depends on redox signaling.

Abstract

Event Abstract Back to Event Expression of ligands for NK cell receptors NKG2D and DNAM-1 on drug-induced senescent Multiple Myeloma cells depends on redox signaling. Biancamaria Ricci1*, Alessandra Soriani1, Maria Luisa Iannitto1, Cinzia Fionda1, Marco Cippitelli1, Stefania Morrone2, Maria Teresa Petrucci3, Maria Rosaria Ricciardi3 and Angela Santoni1 1 "Sapienza" University of Rome, Department of Molecular Medicine, Italy 2 "Sapienza" University of Rome, Department of Experimental Medicine, Italy 3 "Sapienza" University of Rome, Department of Cellular Biotechnologies and Hematology, Italy Natural Killer (NK) cells represent a key component of anti-tumor immune response exhibiting cytotoxic functions and secreting several cytokines and chemokines. Particularly relevant for tumor cell recognition are the activating receptors NKG2D that binds MICA/B and ULBPs, and DNAM1 that recognizes nectin/nectin-like molecules (Nec2 and NecL5/PVR). We have previously demonstrated that NK cells exhibit an enhanced cytotoxic activity against drug-induced senescent Multiple Myeloma (MM) cells due to an increased expression of NKG2DLs and DNAM1Ls. Little is known about the mechanisms underlying the up-regulation of these ligands induced by genotoxic agents. The present study is focused on the identification of the molecular mechanisms underlying NKG2DL and DNAM-1L drug-induced expression on MM cells with particular attention to the role played by changes in the cellular redox state. Our data indicate that low doses of doxorubicin and melphalan can trigger the activation of DNA Damage Response (DDR) and up-regulate NKG2DLs and DNAM1Ls, both at protein and mRNA levels, in an ATM/ATR and Chk1/2-dependent and p53-independent manner. Exposure of MM cells to free radical scavenger N-Acetyl-L-Cysteine (NAC) abrogates DDR activation and senescent associated-cell cycle G2M arrest, induced by doxorubicin and melphalan. Moreover, drug-dependent NKG2DLs and DNAM1Ls induction is inhibited by NAC on both MM cell lines and patient CD138+ malignant plasma cells. Finally, we have demonstrated the involvement of E2F1 transcription factor in the redox signaling-dependent induction of MICA and PVR genes following drug treatment. The finding of new players regulating NK cell activating ligands on tumor cells might provide novel immunotherapeutic tools. References ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A, Foà R, Santoni A. Blood. 2009 Apr 9;113(15):3503-11. doi: 10.1182/blood-2008-08-173914. DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction. Ardolino M, Zingoni A, Cerboni C, Cecere F, Soriani A, Iannitto ML, Santoni A. Blood. 2011 May 5;117(18):4778-86. doi: 10.1182/blood-2010-08-300954. Keywords: NKG2DLs, DNAM1Ls, ROS, DDR, Multiple Myeloma. Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Ricci B, Soriani A, Iannitto M, Fionda C, Cippitelli M, Morrone S, Petrucci M, Ricciardi M and Santoni A (2013). Expression of ligands for NK cell receptors NKG2D and DNAM-1 on drug-induced senescent Multiple Myeloma cells depends on redox signaling.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00271 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Biancamaria Ricci, "Sapienza" University of Rome, Department of Molecular Medicine, Rome, 00161, Italy, biancamaria.ricci@uniroma1.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni Google Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni Google Scholar Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni PubMed Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.