PMID- 32069911 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 12 IP - 2 DP - 2020 Feb 13 TI - Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor. LID - 10.3390/cancers12020440 [doi] LID - 440 AB - Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBalpha blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells. FAU - Mekhloufi, Abdelilah AU - Mekhloufi A AUID- ORCID: 0000-0002-1859-9256 AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Kosta, Andrea AU - Kosta A AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Stabile, Helena AU - Stabile H AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Molfetta, Rosa AU - Molfetta R AUID- ORCID: 0000-0003-2904-6371 AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Zingoni, Alessandra AU - Zingoni A AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Soriani, Alessandra AU - Soriani A AUID- ORCID: 0000-0001-5461-9026 AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Cippitelli, Marco AU - Cippitelli M AUID- ORCID: 0000-0002-9620-538X AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Paolini, Rossella AU - Paolini R AUID- ORCID: 0000-0001-7605-1531 AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Gismondi, Angela AU - Gismondi A AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Ricciardi, Maria Rosaria AU - Ricciardi MR AUID- ORCID: 0000-0002-8772-3521 AD - Division of Hematology, Department of Translational Medicine and Precision, Sapienza University of Rome, 00161 Rome, Italy. FAU - Petrucci, Maria Teresa AU - Petrucci MT AD - Division of Hematology, Department of Translational Medicine and Precision, Sapienza University of Rome, 00161 Rome, Italy. FAU - Masuelli, Laura AU - Masuelli L AD - Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy. FAU - Caracciolo, Giulio AU - Caracciolo G AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Palchetti, Sara AU - Palchetti S AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. FAU - Santoni, Angela AU - Santoni A AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. AD - Neuromed I.R.C.C.S.-Istituto Neurologico Mediterraneo, 86077 Pozzilli, Italy. FAU - Fionda, Cinzia AU - Fionda C AD - Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy. LA - eng GR - 21147/Associazione Italiana per la Ricerca sul Cancro/ GR - 20174T7NXL/Ministero dell'Istruzione, dell'Universita e della Ricerca/ GR - 2017NTK4HY/Ministero dell'Istruzione, dell'Universita e della Ricerca/ PT - Journal Article DEP - 20200213 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC7072437 OTO - NOTNLM OT - IL-8 OT - PVR OT - bone marrow stromal cells OT - multiple myeloma OT - natural killer cells COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2020/02/20 06:00 MHDA- 2020/02/20 06:01 PMCR- 2020/02/13 CRDT- 2020/02/20 06:00 PHST- 2019/12/19 00:00 [received] PHST- 2020/02/10 00:00 [revised] PHST- 2020/02/11 00:00 [accepted] PHST- 2020/02/20 06:00 [entrez] PHST- 2020/02/20 06:00 [pubmed] PHST- 2020/02/20 06:01 [medline] PHST- 2020/02/13 00:00 [pmc-release] AID - cancers12020440 [pii] AID - cancers-12-00440 [pii] AID - 10.3390/cancers12020440 [doi] PST - epublish SO - Cancers (Basel). 2020 Feb 13;12(2):440. doi: 10.3390/cancers12020440.