Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity
// Lavinia Raimondi 1 , Nicola Amodio 1 , Maria Teresa Di Martino 1 , Emanuela Altomare 1 , Marzia Leotta 1 , Daniele Caracciolo 1 , Annamaria Gulla 1 , Antonino Neri 2 , Simona Taverna 3 , Patrizia D’Aquila 4 , Riccardo Alessandro 3 , Antonio Giordano 5 , Pierosandro Tagliaferri 1 and Pierfrancesco Tassone 1,5 . 1 Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy 2 Department of Medical Sciences University of Milan, Hematology1, IRCCS Policlinico Foundation, Milan, Italy 3 Department of Pathology and Forensic and Medical Biotechnology, Section of Biology and…
Bortezomib Induces Anti–Multiple Myeloma Immune Response Mediated by cGAS/STING Pathway Activation
Abstract The proteasome inhibitor bortezomib induces apoptosis in multiple myeloma cells and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine multiple myeloma models, we here show that bortezomib also triggers immunogenic cell death (ICD), characterized by exposure of calreticulin on dying multiple myeloma cells, phagocytosis of tumor cells by dendritic cells, and induction of multiple myeloma–specific immunity. We identify a bortezomib-triggered specific ICD gene signature associated with better outcome in two independent cohorts of patients with multiple myeloma. Importantly, bortezomib stimulates multiple myeloma cell immunogen…
Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma
Abstract Immune therapies including CAR T cells and bispecific T cell engagers are demonstrating remarkable efficacy in relapsed refractory myeloma (MM). In this context, we have recently shown that proteasome inhibitor bortezomib (BTZ) results in immunogenic cell death (ICD) and in a viral mimicry state in MM cells, allowing for immune recognition of tumor cells. Induction of a robust anti-MM immune response after BTZ was confirmed both in vitro and in vivo: treatment of 5TGM1 MM cells with BTZ induced tumor regression associated with memory immune response, confirmed by ELISPOT of mouse splenocytes. We have confirmed the obligate role of calreticulin (CALR) exposure in phagocytosis and th…
Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts.
// Maria Rita Pitari 1 , Marco Rossi 1 , Nicola Amodio 1 , Cirino Botta 1 , Eugenio Morelli 1 , Cinzia Federico 1 , Annamaria Gulla 1 , Daniele Caracciolo 1 , Maria Teresa Di Martino 1 , Mariamena Arbitrio 2 , Antonio Giordano 3, 4 , Pierosandro Tagliaferri 1 , Pierfrancesco Tassone 1, 4 1 Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy 2 ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy 3 Department of Human Pathology and Oncology, University of Siena, Siena, Italy 4 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology,…
A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells.
Abstract Purpose: The onset of drug resistance is a major cause of treatment failure in multiple myeloma. Although increasing evidence is defining the role of miRNAs in mediating drug resistance, their potential activity as drug-sensitizing agents has not yet been investigated in multiple myeloma. Experimental Design: Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan. Results: miR-221/222 expression inversely correlated with melphalan sensitivity of multiple myeloma cells. Inhibition of miR-221/222 overcame melphalan resistance and triggered apoptosis of multiple myeloma cells in vitro, in the presence or absence of…
Myeloid-Derived Suppressor Cells in Multiple Myeloma: Pre-Clinical Research and Translational Opportunities
Immunosuppressive cells have been reported to play an important role in tumor-progression mainly because of their capability to promote immune-escape, angiogenesis, and metastasis. Among them, myeloid-derived suppressor cells (MDSCs) have been recently identified as immature myeloid cells, induced by tumor-associated inflammation, able to impair both innate and adaptive immunity. While murine MDSCs are usually identified by the expression of CD11b and Gr1, human MDSCs represent a more heterogeneous population characterized by the expression of CD33 and CD11b, low or no HLA-DR, and variable CD14 and CD15. In particular, the last two may alternatively identify monocyte-like or granulocyte-lik…