Abstract 543: Regulation of Atherosclerosis by Myeloid-Derived Suppressor Cells

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Amanda C Foks ◽  
Gijs H van Puijvelde ◽  
Vanessa Frodermann ◽  
Thomas van der Heiden ◽  
Ilze Bot ◽  
...  
Keyword(s):  
Immune Responses ◽  
Magnetic Beads ◽  
Immune Therapy ◽  
Atherosclerotic Lesion ◽  
Suppressor Cells ◽  
Lymphoid Tissues ◽  
Dependent Manner ◽  
Myeloid Derived Suppressor Cells ◽  
Immature Myeloid Cells

Objective: Restoration of immune homeostasis in atherosclerosis represents the ultimate goal of an immune-based therapy. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells that potently suppress immune responses in various pathological settings, via multiple mechanisms, including inhibition of T cell responses. They express the myeloid markers CD11b and Gr-1 and can accumulate in various lymphoid and non-lymphoid tissues. In the present study, we determined the role of MDSCs in atherosclerosis by an adoptive transfer of CD11b + Gr-1 + cells into LDLr -/- mice fed a Western-type diet. Methods and Results: We isolated CD11b + Gr-1 + cells from the bone marrow of LDLr -/- mice fed a Western-type diet for 2 weeks with magnetic beads and found that they strongly suppressed αCD3/CD28-induced splenocyte proliferation in an IFN-γ and iNOS-dependent manner. Subsequently, we adoptively transferred MDSCs into LDLr -/- mice fed a Western-type diet for 6 weeks, which resulted in a 35% reduction in atherosclerotic lesion formation in the aortic root. MDSC treatment reduced splenic Th1 and Th17 cells with 50% and diminished B cells, in particular circulating B2 cells, and concomitantly impaired their proliferative capacity. Conclusions: Our data prove that MDSCs could represent a novel cell-based immune-therapy to dampen pro-atherogenic immune responses and thereby reduce atherosclerosis.

scholarly journals Myeloid-derived suppressor cells in hematological malignancies: friends or foes

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Meng Lv ◽  
Ke Wang ◽  
Xiao-jun Huang
Keyword(s):  
Multiple Myeloma ◽  
Immune Responses ◽  
Tumor Immunology ◽  
Hematological Malignancies ◽  
Inflammatory Diseases ◽  
Suppressor Cells ◽  
Multiple Roles ◽  
Myeloid Derived Suppressor Cells ◽  
Hematopoietic Stem ◽  
Immature Myeloid Cells

Abstract Myeloid-derived suppressor cells (MDSCs) are newly identified immature myeloid cells that are characterized by the ability to suppress immune responses and expand during cancer, infection, and inflammatory diseases. Although MDSCs have attracted a lot of attention in the field of tumor immunology in recent years, little is known about their multiple roles in hematological malignancies as opposed to their roles in solid tumors. This review will help researchers better understand the various characteristics and functions of MDSCs, as well as the potential therapeutic applications of MDSCs in hematological malignancies, including lymphoma, multiple myeloma, leukemia, and hematopoietic stem cell transplantation.

scholarly journals Myeloid-Derived Suppressor Cells in Sepsis

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Dengming Lai ◽  
Chaojin Qin ◽  
Qiang Shu
Keyword(s):  
Secondary Infection ◽  
Suppressor Cells ◽  
Antimicrobial Activities ◽  
Therapeutic Benefit ◽  
Myeloid Derived Suppressor Cells ◽  
Innate Immune Responses ◽  
Suspected Infection ◽  
Adaptive Immune ◽  
Immature Myeloid Cells

Sepsis is a systemic, deleterious host response to widespread infection. Patients with sepsis will have documented or suspected infection which can progress to a state of septic shock or acute organ dysfunction. Since sepsis is responsible for nearly 3 million cases per year in China and severe sepsis is a common, expensive fatal condition in America, developing new therapies becomes a significant and worthwhile challenge. Clinical research has shown that sepsis-associated immunosuppression plays a central role in patient mortality, and targeted immune-enhancing therapy may be an effective treatment approach in these patients. As part of the inflammatory response during sepsis, there are elevations in the number of myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous population of immature myeloid cells that possess immunosuppressive activities via suppressing T-cell proliferation and activation. The role of MDSCs in sepsis remains uncertain. Some believe activated MDSCs are beneficial to the sepsis host by increasing innate immune responses and antimicrobial activities, while others think expansion of MDSCs leads to adaptive immune suppression and secondary infection. Herein, we discuss the complex role of MDSCs in immune regulation during sepsis, as well as the potential to target these cells for therapeutic benefit.

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.

scholarly journals Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200111 ◽  
Author(s):  
Mahmoud Mohammad Yaseen ◽  
Nizar Mohammad Abuharfeil ◽  
Homa Darmani ◽  
Ammar Daoud
Keyword(s):  
Immune Responses ◽  
Disease Progression ◽  
Immune Activation ◽  
Pathological Condition ◽  
Suppressor Cells ◽  
Interleukin 10 ◽  
Myeloid Derived Suppressor Cells ◽  
Chronic Infections ◽  
Pathological Conditions

Chronic immune activation and inflammation are unwanted consequences of many pathological conditions, since they could lead to tissue damage and immune exhaustion, both of which can worsen the pathological condition status. In fact, the immune system is naturally equipped with immunoregulatory cells that can limit immune activation and inflammation. However, chronic activation of downregulatory immune responses is also associated with unwanted consequences that, in turn, could lead to disease progression as seen in the case of cancer and chronic infections. Myeloid-derived suppressor cells (MDSCs) are now considered to play a pivotal role in the pathogenesis of different inflammatory pathological conditions, including different types of cancer and chronic infections. As a potent immunosuppressor cell population, MDSCs can inhibit specific and non-specific immune responses via different mechanisms that, in turn, lead to disease persistence. One such mechanism by which MDSCs can activate their immunosuppressive effects is accomplished by secreting copious amounts of immunosuppressant molecules such as interleukin-10 (IL-10). In this article, we will focus on the pathological role of MDSC expansion in chronic inflammatory conditions including cancer, sepsis/infection, autoimmunity, asthma and ageing, as well as some of the mechanisms by which MDSCs/IL-10 contribute to the disease progression in such conditions.

Accumulation of Myeloid-Derived Suppressor Cells in Bone Marrow in Multiple Myeloma Induces Tumor-Specific Immune Suppression and Promotes Tumor Growth

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3954-3954
Author(s):  
Indu R Ramachandran ◽  
Anna Martner ◽  
Thomas C Condamine ◽  
Alexandra Pisklakova ◽  
Tess Chase ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Suppressor Cells ◽  
Cell Responses ◽  
Healthy Donors ◽  
Immature Myeloid Cells ◽  
Time Point

Abstract Abstract 3954 Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells in bone marrow (BM). Accumulation of MM cells in BM is associated with a corresponding dysfunction of local immune responses. The mechanisms involved in the immune suppression remains poorly understood. Myeloid-derived suppressor cells (MDSC) are heterogeneous group of relatively immature myeloid cells characterized by potent immune suppressive activity. However, their role in regulation of immune responses in BM in MM remains unclear. To determine MDSC accumulation in MM patients, BM and blood samples were obtained from newly diagnosed patients and healthy donors. We observed a significant increase in CD11b+ CD33+ CD14− HLA-DRlo MDSCs, but not in CD11b+ CD33+ CD14+ HLA-DRhi monocytes, in the blood and BM of patients as compared to cells with the same phenotype in healthy donors. MDSC isolated from patient BM suppressed T cell responses as measured by IFN-g Elispot assays of mixed leukocyte reactions. Immature myeloid cells with the same phenotype from BM of healthy donor did not inhibit T cells. The possible role of MDSC in MM progression was further evaluated in mouse model of MM. Three different MM cell lines (BCM, DP42 and ATLN) obtained from Dr Van Ness (University of Minnesota) were used. MM tumors were established by i.v. injection of syngeneic mice. We observed an expansion of CD11b+ GR1+ MDSCs (up to 70%) in the BM of tumor-bearing (TB) mice within one week after injection of tumor cells. MDSC purified from BM of TB mice at that time point potently suppressed antigen-specific T cell proliferation and IFN-g production. As tumor progressed, CD138+ MM cells expanded (up to 90%) in the BM replacing normal BM cells including MDSC. However, at later time points (2–3 weeks), MDSC expansion was seen in spleen and lymph nodes of TB mice. To evaluate the possible role of MDSC in MM progression, we used S100A9 knockout (KO) mice. S100A9 plays an important role in MDSC accumulation in cancer and S100A9 KO TB mice had reduced accumulation of these cells. When wild-type (WT) and S100A9 KO mice were inoculated with DP42 cells no differences in tumor growth and survival were observed. S100A9 KO mice had a decrease in MDSC accumulation in the BM of TB mice compared to WT mice. Additionally, MDSC from S100A9 KO mice failed to suppress antigen-specific T cells ex vivo, whereas MDSC from WT TB mice did. To evaluate the development of antigen-specific immune responses in MM, we generated a MM cell line over-expressing the chicken ovalbumin protein (DP42-OVA). S100A9 KO mice injected with the immunogenic DP42-OVA cell line showed significantly delayed tumor growth and improved survival as compared with WT mice. Further analysis of T cell responses in vivo showed increased accumulation of antigen-specific T cells within the BM of S100A9 KO mice, but not WT mice, as early as one week post-tumor inoculation. Antigen-specific T cells in spleens were not detected at that time point. These cells were seen in spleens on S100A9 KO mice only 2–3 weeks after tumor injection. Thus, our study demonstrated that MM is associated with rapid accumulation of MDSC with potent immune suppressive activity against tumor-specific T cells. Our data directly suggest that targeting MDSC in MM may improve antitumor immune response and clinical outcome of the disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Myeloid-derived suppressor cells and their role in gynecological malignancies

Tumor Biology ◽  
2018 ◽  
Vol 40 (7) ◽  
pp. 101042831877648 ◽  
Author(s):  
Seiji Mabuchi ◽  
Eriko Yokoi ◽  
Naoko Komura ◽  
Tadashi Kimura
Keyword(s):  
Immune Responses ◽  
Current Knowledge ◽  
Gynecological Cancer ◽  
Suppressor Cells ◽  
Heterogeneous Population ◽  
Cancer Therapies ◽  
Myeloid Derived Suppressor Cells ◽  
Immunosuppressive Activity ◽  
Anti Cancer ◽  
Immature Myeloid Cells

Myeloid-derived suppressor cells are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity (they block the proliferation and activity of both T cells and natural killer cells). In addition to their role in suppressing immune responses, myeloid-derived suppressor cells directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In the area of gynecological cancer, increased numbers of circulating myeloid-derived suppressor cells or tumor-infiltrating myeloid-derived suppressor cells have been detected, and the increased frequencies of myeloid-derived suppressor cells are associated with a poor prognosis. Thus, the successful myeloid-derived suppressor cells depletion may hold the key to maximizing existing anti-cancer therapies and improving the prognosis of gynecological cancer. In this review, we summarize current knowledge regarding myeloid-derived suppressor cells biology, clinical significance of myeloid-derived suppressor cells, and the potential myeloid-derived suppressor cells–targeting strategies in gynecological cancer.

scholarly journals Role of myeloid-derived suppressor cells in the promotion and immunotherapy of colitis-associated cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000609
Author(s):  
Yungang Wang ◽  
Yanxia Ding ◽  
Yijun Deng ◽  
Yu Zheng ◽  
Shengjun Wang
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Regulatory Network ◽  
Suppressor Cells ◽  
Therapeutic Strategies ◽  
Heterogeneous Population ◽  
Myeloid Derived Suppressor Cells ◽  
Immature Myeloid Cells ◽  
Inflammatory Bowel

Colitis-associated cancer (CAC) is a specific type of colorectal cancer that develops from inflammatory bowel disease (IBD). Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are essential for the pathological processes of inflammation and cancer. Accumulating evidence indicates that MDSCs play different but vital roles during IBD and CAC development and impede CAC immunotherapy. New insights into the regulatory network of MDSCs in the CAC pathogenesis are opening new avenues for developing strategies to enhance the effectiveness of CAC treatment. In this review, we explore the role of MDSCs in chronic inflammation, dysplasia and CAC and summarize the potential CAC therapeutic strategies based on MDSC blockade.

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

scholarly journals The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

Vaccines ◽  
2016 ◽  
Vol 4 (4) ◽  
pp. 36 ◽  
Author(s):  
Viktor Umansky ◽  
Carolin Blattner ◽  
Christoffer Gebhardt ◽  
Jochen Utikal
Keyword(s):  
Cancer Progression ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells
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