ADAM10 CONTRIBUTES TO MICA/B SHEDDING FROM MULTIPLE MYELOMA CELLS IN RESPONSE TO GENOTOXIC STRESS

Abstract

Event Abstract Back to Event ADAM10 CONTRIBUTES TO MICA/B SHEDDING FROM MULTIPLE MYELOMA CELLS IN RESPONSE TO GENOTOXIC STRESS Francesca Cecere1*, Alessandra Zingoni1*, Elisabetta Vulpis1, Rosa Molfetta1, Alessandra Soriani1, Cinzia Fionda1, Maria Teresa Petrucci2, Maria Rosaria Ricciardi2, Rossella Paolini1, Marco Cippitelli1 and Angela Santoni1 1 "Sapienza" University of Rome, Molecular Medicine, Italy 2 "Sapienza" University of Rome, Hematology, Italy The MHC class I-related chain MICA/B ligands for the activating receptor NKG2D can be shed from tumor cells and their presence in sera is associated with impaired NK and CTL effector functions and disease progression. We showed that multiple myeloma (MM) cells up-regulate surface expression of NKG2D ligands after treatment with low doses of chemotherapeutic drugs and become more susceptible to NK cell lysis. Here, we investigated whether drug treatment of MM cells could result in MICA/B release. Soluble MICB was up-regulated after drug treatment and the ADAM10 specific inhibitor GI254023X dramatically reduced MICB shedding in a dose-dependent manner and was accompanied by a concomitant increase of cell-surface MICB. Similar results were obtained by shRNA-mediated gene silencing. Remarkably, chemotherapeutic agents increased ADAM10 expression either in MM cell lines or in ex-vivo malignant CD138+/CD38+ plasma cells. Regarding MICA, since its polymorphism can affect the shedding process, we investigated the effect of chemotherapeutic agents on the release of two allelic variants of MICA: MICA*019 and MICA*008 which represent the prototype of the long and short form of the MICA alleles, respectively. Similarly to MICB, drug treatment stimulated MICA*019 shedding with an ADAM10 dependent mechanism while didn’t affect MICA*008 release. Our findings indicate that chemotherapeutic drugs not only enhance MICA/B surface expression on MM cells, but also promote their shedding. The MICA genotype and the relative contribution of membrane associated vs soluble MICA/B in NKG2D dependent mechanisms of NK cell recognition of MM cells, should be considered to design NK cell-based immunochemotherapeutic approaches. References Soriani, A., Zingoni, A., Cerboni, C., Iannitto, M.L., Ricciardi, M.R., Di Gialleonardo, V., Cippitelli, M., Fionda, C., Petrucci, M.T., Guarini, A., Foa’, R., Santoni, A. (2009). 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. Blood, 113, 3503-3511. Keywords: Natural Killer cells, NKG2D, Metalloproteinases, Multiple Myeloma, MICA polymorphism Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Cecere F, Zingoni A, Vulpis E, Molfetta R, Soriani A, Fionda C, Petrucci M, Ricciardi M, Paolini R, Cippitelli M and Santoni A (2013). ADAM10 CONTRIBUTES TO MICA/B SHEDDING FROM MULTIPLE MYELOMA CELLS IN RESPONSE TO GENOTOXIC STRESS. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00115 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: 11 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Francesca Cecere, "Sapienza" University of Rome, Molecular Medicine, Rome, Italy, francesca.cecere@uniroma1.it Dr. Alessandra Zingoni, "Sapienza" University of Rome, Molecular Medicine, Rome, Italy, alessandra.zingoni@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 Francesca Cecere Alessandra Zingoni Elisabetta Vulpis Rosa Molfetta Alessandra Soriani Cinzia Fionda Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni Google Francesca Cecere Alessandra Zingoni Elisabetta Vulpis Rosa Molfetta Alessandra Soriani Cinzia Fionda Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni Google Scholar Francesca Cecere Alessandra Zingoni Elisabetta Vulpis Rosa Molfetta Alessandra Soriani Cinzia Fionda Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni PubMed Francesca Cecere Alessandra Zingoni Elisabetta Vulpis Rosa Molfetta Alessandra Soriani Cinzia Fionda Maria Teresa Petrucci Maria Rosaria Ricciardi Rossella Paolini Marco Cippitelli Angela Santoni Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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