title: Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells.
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.
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Kim
authors: K
authors: De Veirman
authors: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.|Myeloid Cell Immunology Laboratory, VIB, Brussels, Belgium.
authors: Jo A
authors: JA
authors: Van Ginderachter
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Susanne
authors: S
authors: Lub
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Nathan
authors: N
authors: De Beule
authors: Department of Immunology-Physiology, Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Kris
authors: K
authors: Thielemans
authors: Gerontology & Frailty in Ageing Departments, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Ivan
authors: I
authors: Bautmans
authors: Department of Cellular & Structural Biology and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, USA.
authors: Babatunde O
authors: BO
authors: Oyajobi
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Elke
authors: E
authors: De Bruyne
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Eline
authors: E
authors: Menu
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Miguel
authors: M
authors: Lemaire
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Ivan
authors: I
authors: Van Riet
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Karin
authors: K
authors: Vanderkerken
authors: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors: Els
authors: E
authors: Van Valckenborgh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein
keywords: generation; mechanism; multiple myeloma; myeloid-derived suppressor cells; targeting