scholarly journals Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4729-4739 ◽  
Author(s):  
Dan Ilkovitch ◽  
Diana M. Lopez
Keyword(s):  
Tumor Cells ◽  
Critical Role ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Arginase 1 ◽  
Antitumor Properties ◽  
Tumor Expression

Abstract The transmembrane isoform of mucin 1 (MUC1/TM) is a well-recognized tumor antigen, contributing to tumorigenesis and immune evasion. Although MUC1/TM has been correlated with malignancy, we have previously reported on antitumor properties and prevention of tumor development by a secreted splice variant of MUC1 (MUC1/sec). Because myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-induced immunosuppression, we investigated their recruitment by tumor cells expressing either MUC1/TM or MUC1/sec. DA-3 tumor cells expressing MUC1/sec recruit dramatically lower levels of MDSCs, relative to MUC1/TM-expressing DA-3 cells. Because MUC1/sec was previously shown to down-regulate tumor expression of urokinase plasminogen activator (uPA), a protease linked to tumor aggressiveness and metastasis, the potential role of uPA in MDSC recruitment was investigated. Tumor-derived uPA is capable of recruiting MDSCs, and correlates with tumor development. In addition to diminishing recruitment of MDSCs, the effect of MUC1/sec on MDSC-suppressive mechanisms was investigated. MUC1/sec, or its unique immunoenhancing peptide, is capable of blocking expression of arginase 1 and production of reactive oxygen species in MDSCs, implicated in the suppression of T cells. These findings demonstrate a new mechanism of MDSC recruitment, and provide evidence that MUC1/sec has antitumor properties affecting MDSCs.

scholarly journals TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host

2021 ◽  
Vol 12 ◽  
Author(s):  
Ge Song ◽  
Yue Zhang ◽  
Jie Tian ◽  
Jie Ma ◽  
Kai Yin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Critical Role ◽  
Tumor Necrosis Factor Receptor ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Lung Cancer Patients ◽  
Tumor Bearing ◽  
Arginase 1 ◽  
Antitumor Immunotherapy ◽  
Transcription 3

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous cells derived from the bone marrow and they are the major component of the tumor-induced immunosuppressive environment. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, catalyzes the polyubiquitination of target proteins. TRAF6 plays a critical role in modulating the immune system. However, whether TRAF6 is involved in the regulation of MDSCs has not been thoroughly elucidated to date. In this study, we found that the expression of TRAF6 in MDSCs derived from tumor tissue was significantly upregulated compared with that of MDSCs from spleen of tumor-bearing mice. Knockdown of TRAF6 remarkably attenuated the immunosuppressive effects of MDSCs. Mechanistically, TRAF6 might improve the immunosuppression of MDSCs by mediating K63-linked polyubiquitination and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Additionally, it was discovered that the accumulation of MDSCs was abnormal in peripheral blood of lung cancer patients. TRAF6 and arginase 1 were highly expressed in MDSCs of patients with lung cancer. Taken together, our study demonstrated that TRAF6 participates in promoting the immunosuppressive function of MDSCs and provided a potential target for antitumor immunotherapy.

scholarly journals AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner

2020 ◽  
Vol 21 (24) ◽  
pp. 9613
Author(s):  
Wurood Hantoosh Neamah ◽  
Philip Brandon Busbee ◽  
Hasan Alghetaa ◽  
Osama A. Abdulla ◽  
Mitzi Nagarkatti ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Critical Role ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Dependent Manner ◽  
Myeloid Derived Suppressor Cells ◽  
Aryl Hydrocarbon ◽  
Cxc Chemokine ◽  
Consequent Effect

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.

Abstract 3646: The role of myeloid-derived suppressor cells in tumor development

2011 ◽  
Author(s):  
Myrna L. Ortiz ◽  
Pingyan Cheng ◽  
Noreen Luetteke ◽  
Je-In Youn ◽  
Dmitry I. Gabrilovich
Keyword(s):  
Tumor Development ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Phenotypic and Functional Diversities of Myeloid-Derived Suppressor Cells in Autoimmune Diseases

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Huijuan Ma ◽  
Chang-Qing Xia
Keyword(s):  
Autoimmune Diseases ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Beneficial Effects ◽  
Adaptive Immune ◽  
The Past ◽  
Animal Tumor ◽  
Promote Tumor Development

Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of cells with the function to suppress innate as well as adaptive immune responses. The initial studies of MDSCs were primarily focused on the field of animal tumor models or cancer patients. In cancer, MDSCs play the deleterious role to inhibit tumor immunity and to promote tumor development. Over the past few years, an increasing number of studies have investigated the role of MDSCs in autoimmune diseases. The beneficial effects of MDSCs in autoimmunity have been reported by some studies, and thus, immunosuppressive MDSCs may be a novel therapeutic target in autoimmune diseases. There are some controversial findings as well. Many questions such as the activation, differentiation, and suppressive functions of MDSCs and their roles in autoimmune diseases remain unclear. In this review, we have discussed the current understanding of MDSCs in autoimmune diseases.

scholarly journals Heterogeneous Myeloid Cells in Tumors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3772
Author(s):  
Aixia Dou ◽  
Jing Fang
Keyword(s):  
Cancer Therapy ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Clonal Evolution ◽  
Critical Role ◽  
Tumor Development ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Main Function ◽  
Opposing Effects

Accumulating studies highlight a critical role of myeloid cells in cancer biology and therapy. The myeloid cells constitute the major components of tumor microenvironment (TME). The most studied tumor-associated myeloid cells (TAMCs) include monocytes, tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-related circulating neutrophils, tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). These heterogenous myeloid cells perform pro-tumor or anti-tumor function, exerting complex and even opposing effects on all stages of tumor development, such as malignant clonal evolution, growth, survival, invasiveness, dissemination and metastasis of tumor cells. TAMCs also reshape TME and tumor vasculature to favor tumor development. The main function of these myeloid cells is to modulate the behavior of lymphocytes, forming immunostimulatory or immunosuppressive TME cues. In addition, TAMCs play a critical role in modulating the response to cancer therapy. Targeting TAMCs is vigorously tested as monotherapy or in combination with chemotherapy or immunotherapy. This review briefly introduces the TAMC subpopulations and their function in tumor cells, TME, angiogenesis, immunomodulation, and cancer therapy.

scholarly journals Increased Levels of Granulocytic Myeloid-Derived Suppressor Cells in Peripheral Blood and Tumour Tissue of Pancreatic Cancer Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Yazan S. Khaled ◽  
Basil J. Ammori ◽  
Eyad Elkord
Keyword(s):  
Pancreatic Cancer ◽  
Suppressor Cells ◽  
Blood Levels ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1 ◽  
Hla Dr ◽  
Healthy Donors ◽  
And Function ◽  
Immunosuppressive Cells

Pancreatic cancer (PC) often presents late with poor survival. While role of immunosuppressive cells in preclinical studies provided help to develop immunotherapeutic agents, these cells remain under investigation in PC. The aim of this study was to characterise the different subsets of myeloid-derived suppressor cells (MDSCs) and evaluate their level and function in the circulation and tissue of PC patients. Significant increases in circulating and tumour-infiltrating granulocytic (Lin-HLA-DR-CD33+CD11b+CD15+), but not monocytic (Lin-HLA-DR-CD14+), MDSCs were detected in PC patients when compared with healthy donors and patients with chronic pancreatitis. The circulating MDSCs from PC patients expressed arginase 1, which represents their functional state. Blood levels of MDSCs showed no association with PC stage or preoperative levels of tumour markers. These findings provide a first characterisation of the phenotype of different subsets of peripheral and local MDSCs in PC patients and suggest that the frequency and contribution of these cells are predominantly granulocytic. This information demonstrates that MDSCs play a role in pancreatic cancer and future large validation studies may help in the development of new immunotherapeutic strategies to inhibit or eliminate MDSC function.

Microenvironment Induced Myelodysplastic Syndrome (MDS) in S100A9 Transgenic Mice Caused by Myeloid-Derived Suppressor Cells (MDSC)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 788-788 ◽  
Author(s):  
Sheng Wei ◽  
Xianghong Chen ◽  
Junmin Zhou ◽  
Ling Zhang ◽  
Nicole R. Fortenbery ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Myelodysplastic Syndrome ◽  
Colony Formation ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Suppressor Cells ◽  
Inflammatory Factor ◽  
Myeloid Derived Suppressor Cells

Abstract Abstract 788 Understanding the pathophysiology of myelodysplastic syndrome (MDS) is limited by a complex molecular mechanism and lack of an adequate animal model that recapitulates the role of inflammation in the abnormal hematopoiesis. We recently showed that patients with MDS have expansion of inflammation-related hematopoietic suppressive cells called immature myeloid-derived suppressor cells (MDSC) that display direct cytotoxic and suppressive effects on autologous hematopoietic progenitor cells (HPCs). Expansion of bone marrow (BM) MDSCs contributed to the production of inflammatory cytokines and reduced HPC survival underlying BM failure in lower risk patients. Here we provide evidence that MDSC activation, expansion and development is driven by overexpression of inflammatory-related signaling molecules, myeloid-related protein 8 (MRP8, encoded by S100A8) and MRP14 (encoded by S100A9). Both MRP proteins serve as the native endogenous ligands for Toll-like receptor 4 (TLR4), which is an important damage-associated molecular pattern (DAMP) mediating inflammatory response. We found higher expression of MRP8 and MRP14 in BM mononuclear cells from MDS patients compared to healthy donors, in whom these proteins were not detectable. High surface expression of both TLR2 and TLR4 in MDS MDSCs compared to healthy donor MDSCs confirmed that this signaling pathway is activated in MDS. Inhibition of MRP8/MRP14 proteins in MDSCs using specific shRNAs dramatically attenuated IL-10 and TGF-β production and rescued BFU-E and CFU-GM colony formation of autologous bone marrow progenitors. These data show that inflammation-associated MRP8/MRP14 expression plays a critical role in the suppressive activities of MDS MDSCs. We therefore generated S100A9 transgenic mice (S100A9Tg) overexpressing the murine MRP14 homologue and investigated the role of this protein in bone marrow failure. Significant MDSC accumulation was evident in the BM of S100A9Tg mice by 6 weeks, but not in S100 knockout (KO) or wild type (WT) mice. Similar to human MDS, MDSCs from S100A9Tg mice, but not S100KO or WT mice, significantly inhibited BFU-E colony formation. Depletion of MDSCs in vitro rescued BM colony formation in the S100A9Tg mice indicating that the BM suppression is mediated by MDSC cells. TGF-β and IL-10 secretion was significantly increased in S100A9Tg mice, substantiating the role of S100A9 as an essential inflammatory factor that regulating MDSC suppressive activity. Analogous to human MDS, 6-month old S100A9Tg mice developed ineffective hematopoiesis with severe anemia, leukopenia, and thrombocytopenia accompanied by MDS-like morphological features. BM aspirates and core biopsies from S100A9Tg mice were hypercellular with trilineage cytological dysplasia characteristic of MDS. Treatment with ATRA, which induced the differentiation of MDSCs rescued hematopoiesis in S100A9Tg mice. Our findings indicate that primary BM expansion of MDSC is sufficient to perturb hematopoiesis and result in the development of MDS, supporting the notion of microenvironment-conducive oncogenesis. S100A9Tg transgenic mice provide a novel in vivo model of human MDS for target discovery and testing of novel therapeutics. Disclosures: No relevant conflicts of interest to declare.

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