The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells
Abstract
// Jinheng Wang 1 , Kim De Veirman 1 , Nathan De Beule 1 , Ken Maes 1 , Elke De Bruyne 1 , Els Van Valckenborgh 1 , Karin Vanderkerken 1, * , Eline Menu 1, * 1 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium * These authors have equally contributed to this work Correspondence to: Eline Menu, e-mail: [email protected] Keywords: multiple myeloma, bone marrow stromal cells, exosomes, myeloid-derived suppressor cells, immunosuppression Received: July 17, 2015 Accepted: October 23, 2015 Published: November 02, 2015 ABSTRACT Exosomes, extracellular nanovesicles secreted by various cell types, modulate the bone marrow (BM) microenvironment by regulating angiogenesis, cytokine release, immune response, inflammation, and metastasis. Interactions between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells play crucial roles in MM development. We previously reported that BMSC-derived exosomes directly promote MM cell growth, whereas the other possible mechanisms for supporting MM progression by these exosomes are still not clear. Here, we investigated the effect of BMSC-derived exosomes on the MM BM cells with specific emphasis on myeloid-derived suppressor cells (MDSCs). BMSC-derived exosomes were able to be taken up by MM MDSCs and induced their expansion in vitro . Moreover, these exosomes directly induced the survival of MDSCs through activating STAT3 and STAT1 pathways and increasing the anti-apoptotic proteins Bcl-xL and Mcl-1. Inhibition of these pathways blocked the enhancement of MDSC survival. Furthermore, these exosomes increased the nitric oxide release from MM MDSCs and enhanced their suppressive activity on T cells. Taken together, our results demonstrate that BMSC-derived exosomes activate MDSCs in the BM through STAT3 and STAT1 pathways, leading to increased immunosuppression which favors MM progression.