Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells

// Kim De Veirman 1 , Jo A. Van Ginderachter 2, 3 , Susanne Lub 1 , Nathan De Beule 1 , Kris Thielemans 4 , Ivan Bautmans 5 , Babatunde O. Oyajobi 6 , Elke De Bruyne 1 , Eline Menu 1 , Miguel Lemaire 1 , Ivan Van Riet 1 , Karin Vanderkerken 1, * , Els Van Valckenborgh 1, * 1 Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium 2 Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium 3 Myeloid Cell Immunology Laboratory, VIB, Brussels, Belgium 4 Department of Immunology-Physiology, Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium 5 Gerontology & Frailty in Ageing Departments, Vrije Universiteit Brussel, Brussels, Belgium 6 Department of Cellular & Structural Biology and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, USA * These authors have contributed equally to this work Correspondence to: Els Van Valckenborgh, e-mail: Els.Van.Valckenborgh@vub.ac.be Keywords: multiple myeloma, myeloid-derived suppressor cells, generation, mechanism, targeting Received: January 26, 2015      Accepted: February 08, 2015      Published: March 23, 2015 ABSTRACT Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC survival was observed in the presence of MM-conditioned medium. Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival. In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.