Myeloid-Derived Suppressor Cells Regulate Growth of Multiple Myeloma by Inhibiting T Cells in Bone Marrow

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
The Journal of Immunology (Impact Factor: 4.92). 03/2013; 190(7). DOI: 10.4049/jimmunol.1203373
Source: PubMed


Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the immune response in cancer. However, their role in bone marrow (BM), the site of primary localization of multiple myeloma (MM), is poorly understood. In this study, we found a significant accumulation of CD11b+CD14-CD33+ immunosuppressive MDSC in BM of patients with newly diagnosed MM. To assess the possible role of MDSC in MM, we used immunocompetent mouse models. Immunosuppressive MDSC accumulated in BM of mice as early as 1 wk after tumor inoculation. S100A9 knockout (KO) mice, which are deficient in their ability to accumulate MDSC in tumor-bearing hosts, demonstrated reduced MDSC accumulation in BM after injection of MM cells compared with wild-type mice. Growth of the immunogenic MM cells was significantly reduced in S100A9KO mice. This effect was associated with the accumulation of Ag-specific CD8+ T cells in BM and spleens of S100A9KO mice, but not wild-type mice, and was abrogated by the administration of anti-CD8 Ab or adoptive transfer of MDSC. Thus, the accumulation of MDSC at early stages of MM plays a critical role in MM progression and suggests that MDSC can be considered a possible therapeutic target in this disease.

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    • "Moreover, although the immune system in general suppresses multiple myeloma [72], not all immune cells mediate this role. Regulatory T-cells and immunosuppressive myeloidderived suppressor cells [73] are now being identified as important new targets that inhibit the immune response in multiple myeloma [74]. Interestingly, cellular immunity was found to be decreased in myeloma patients, including decreased ratio of CD4 "
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    ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. Copyright © 2015. Published by Elsevier Inc.
    Bone 02/2015; 75. DOI:10.1016/j.bone.2015.02.021 · 3.97 Impact Factor
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    • "Using another immunocompetent mouse model, established by intravenous inoculation of BCM, DP42, or ATLN MM cells into syngeneic mice, MDSC accumulated in BM as early as 1 week after tumor inoculation. When these mice were engineered to lose their ability to accumulate MDSC in tumor-bearing hosts (S100A9 knockout), growth of the immunogenic MM cells was significantly reduced showing again that the accumulation of MDSC at early stages of MM plays a critical role in MM progression [87]. In the ATLN model, a significant increase in the proportion and absolute number of MDSC in BM was observed as early as 1 week after tumor cell inoculation, followed in weeks 2-3 by a reduction due to MM expansion in BM and a progressive increase in spleen and lymphonodes. "
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    ABSTRACT: Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.
    BioMed Research International 06/2014; 2014(7):198539. DOI:10.1155/2014/198539 · 2.71 Impact Factor
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    • "In humans, MDSCs are most commonly defined as CD14−CD11b+ cells, or more narrowly, as cells that express the common myeloid marker CD33 but lack the expression of markers of mature myeloid and lymphoid cells and HLA-DR (Gabrilovich and Nagaraj, 2009). Most studies have concluded that the human MDSC phenotype is Lin−HLA-DR−CD33+ or CD11b+CD14−CD33+ (Almand et al., 2001; Filipazzi et al., 2012; Gabrilovich and Nagarai, 2009; Kotsakis et al., 2012; Ramachandran et al., 2013; Vasquez-Dunddel et al., 2013); we utilized Lin1−HLA-DR−CD33+CD11b+ as markers of MDSCs in this study. "
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    ABSTRACT: Myeloid-derived suppressor cells (MDSCs) play an important role in impairing the function of T cells. We characterized MDSCs in two chronic hepatitis C (CHC) cohorts: a cross-sectional group that included 61 treatment-naive patients with CHC, 14 rapid virologic response (RVR) cases and 22 early virologic response (EVR) cases; and a longitudinal group of 13 cases of RVR and 10 cases of EVR after pegylated-interferon-α/ribavirin treatment for genotype 1b HCV infection. Liver samples from 32 CHC patients and six healthy controls were subjected to immunohistochemical analysis. MDSCs frequency in treatment-naive CHC was significantly higher than in RVR, EVR, or healthy subjects and was positively correlated with HCV RNA. Patients infected with HCV genotype 2a had a significantly higher frequency of MDSCs than those infected with genotype 1b. Decreased T cell receptor (TCR) ζ expression on CD8(+) T cells was significantly associated with an increased frequency of MDSCs in treatment-naive CHC patients and was restored by L-arginine treatment in vitro. Increased numbers of liver arginase-1(+) cells were closely associated with the histological activity index in CHC. The TCR ζ chain was significantly downregulated on hepatic CD8(+) T cells in CHC. During antiviral follow up, MDSCs frequency in peripheral blood mononuclear cells was directly correlated with the HCV RNA load in the plasma and inversely correlated with TCR ζ chain expression in CD8(+) T cells in both RVR and EVR cases. Notably, the RVR group had a higher frequency of MDSCs at baseline than the EVR group. Collectively, this study provides evidence that MDSCs might be associated with HCV persistence and downregulation of CD8 ζ chain expression.
    Moleculer Cells 01/2014; 37(1):66-73. DOI:10.14348/molcells.2014.2282 · 2.09 Impact Factor
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