Myeloid-Derived Suppressor Cells Regulate Growth of Multiple Myeloma by Inhibiting T Cells in Bone Marrow.
ABSTRACT 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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ABSTRACT: Study of myeloid cells endowed with suppressive activity is an active field of research which has particular importance in cancer, in view of the negative regulatory capacity of these cells to the host's immune response. The expansion of these cells, called myeloid-derived suppressor cells (MDSCs), has been documented in many models of tumor-bearing mice and in patients with tumors of various origin, and their presence is associated with disease progression and reduced survival. For this reason, monitoring this type of cell expansion is of clinical importance, and flow cytometry is the technique of choice for their identification. Over the years, it has been demonstrated that MDSCs comprise a group of immature myeloid cells belonging both to monocytic and granulocytic lineages, with several stages of differentiation; their occurrence depends on tumor-derived soluble factors, which guide their expansion and determine their block of differentiation. Because of their heterogeneous composition, accurate phenotyping of these cells requires a multicolor approach, so that the expansion of all MDSC subsets can be appreciated.This review article focuses on identifying MDSCs and discusses problems associated with phenotyping circulating and tumor-associated MDSCs in humans and in mouse models. This article is protected by copyright. All rights reserved.Cytometry Part B Clinical Cytometry 11/2014; 88(2). DOI:10.1002/cytob.21206 · 2.28 Impact Factor
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ABSTRACT: Survivin is a small protein inhibitor of apoptosis and a tumor associated antigen. Survivin expression in multiple myeloma is associated with poor prognosis, disease progression, and drug resistance. The CD4+ response against survivin remains uncharacterized. In order to better understand the anti-tumor immune response to survivin, and optimize vaccination strategies, we characterized the spontaneous CD4+CD25- T cell response against survivin in healthy donors and myeloma patients using survivin derived peptide pools. Healthy donors and myeloma patients' CD4+CD25- T cells exhibited a proliferative and IFN-gamma response against survivin peptides loaded onto autologous dendritic cells. We employed limiting dilution analysis to quantify the precursor frequency of survivin reactive CD4+CD25- T cells. Multiple myeloma patients (range 0% to 2.2x10(-3)%, n=12) had fewer survivin reactive CD4+CD25- T cells than healthy blood donors (range 1.1x10(-3) to 8.4x10(-3)%, n=10), p = 0.021. The survivin reactive CD4+CD25- T cell precursor frequency was inversely associated with tumor survivin mRNA expression (p = 0.0028, r = -1.0, n = 6), and survivin tumor protein expression by IHC (p = 0.0295, r = -0.67, n = 10). A full length mutant survivin protein-pulsed dendritic cell vaccine expanded survivin reactive CD4+CD25- T cells after 12 days of in vitro culture (range 0-540x,median = 42x), and expansion was achieved even in patients with low baseline survivin reactive CD4+ precursors. We have, for the first time, quantified the circulating CD4+CD25- precursor frequency against survivin and demonstrated this is lower in myeloma patients than healthy donors. The number of survivin reactive CD4+CD25- T cells is inversely associated with tumor survivin expression suggesting suppression of survivin responsive CD4+CD25- T cells. Further exploration of a full length mutant survivin protein vaccine which expands survivin reactive CD4+ cells independent of the survivin reactive precursor frequency is warranted.05/2015; 3(1). DOI:10.1186/s40425-015-0065-1
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ABSTRACT: Growth arrest and DNA damage-inducible protein (GADD34/Ppp1r15a) is induced by various stimuli including DNA damage and ER stress. DNA damage and oncogene activation, accompanied by tumor-specific DNA repair defects and a failure to stall the cell cycle, are early markers of hepatocellular carcinoma (HCC). However, whether GADD34 accounts for regulating HCC tumorigenesis remains elusive. Here, we demonstrated that GADD34 expression was upregulated in the liver of mice after exposure to a carcinogen, diethylnitrosamine (DEN). In both acute and chronic DEN treatment models, GADD34 deficiency not only decreased oncogene expression, but also reduced hepatic damage. Moreover, loss of GADD34 attenuated immune cell infiltration, pro-inflammatory cytokine expression and hepatic compensatory proliferation. Finally, GADD34-deficient mice showed impaired hepatocarcinogenesis. Thus, the process of DEN-induced HCC proceeded as follows. First, DEN treatment induced DNA damage in hepatocytes, resulting in elevated expression of GADD34 in the liver. The increased expression of GADD34 augmented hepatic necrosis followed by elevated expression of interleukin (IL)-1β and monocyte chemoattractant protein 1. This process promoted immune cell infiltration and Kupffer cell/macrophage activation followed by production of reactive oxygen species and pro-tumorigenic cytokines such as IL-6 and tumor necrosis factor-α. The pro-tumorigenic cytokines stimulated compensatory proliferation of surviving and mutant hepatocytes. Together with oncogene c-Myc expression, these processes led to HCC. Our results suggest therapeutic opportunities for HCC by targeting GADD34-related pathways.Cancer Immunology and Immunotherapy 04/2015; DOI:10.1007/s00262-015-1690-8 · 3.94 Impact Factor