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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    • "We and others have previously demonstrated that development of MM is associated with accumulation in BM of myeloidderived suppressor cells (MDSCs) [1] [2] [3] [4] [5]. These cells are morphologically and phenotypically similar to immature neutrophils or monocytes but distinct in functional and biochemical characteristics and in their ability to suppress immune responses [6]. "
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    ABSTRACT: Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM-bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN-MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell-cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM.
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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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    • "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.
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