Impact Of Myeloid-derived Suppressor Cells Research Articles

MDSC expansion during HIV infection: regulators, ART and immune reconstitution.

Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.

Expansion of Monocytic Myeloid-Derived Suppressor Cells in Patients Under Hemodialysis Might Lead to Cardiovascular and Cerebrovascular Events

BackgroundThe specific mechanism of cardiovascular and cerebrovascular vasculopathy in the context of end-stage renal disease has not been elucidated. In the present study, we investigated the clinical impact of myeloid-derived suppressor cells (MDSCs) on hemodialysis patients and their mechanism of action.MethodsMDSCs were tested among 104 patients undergoing hemodialysis and their association with overall survival (OS) and cardiovascular and cerebrovascular events was determined.ResultsHemodialysis patients presented a significantly higher level of monocytic MDSCs (M-MDSCs) compared to healthy controls. M-MDSC were tested 3 months after first testing among 103 hemodialysis patients, with one patient not retested due to early death. The repeated results of M-MDSC levels were consistent with the initial results. Patients with persistent high level of M-MDSCs presented decreased OS, as well as increased stroke and acute heart failure events. As illustrated by multivariate Cox regression, M-MDSC was an independent predictor for OS and stroke events of hemodialysis patients. T cell proliferations were significantly abrogated by hemodialysis-related M-MDSCs in a dose-dependent manner. Besides, M-MDSCs presented higher levels of CXCR4 and VLA-4 compared to monocytes, which indicated their enhanced capability to be recruited to atherosclerotic lesions. The expression of arginase I and activity of arginase was also significantly raised in hemodialysis-related M-MDSCs. Human coronary arterial endothelial cells (HCAECs) presented increased capability to migration by coculture with M-MDSCs, compared with monocyte group. Arginase inhibitor and L-arginine abrogated the immune suppressive function and induction of HCAECs migration of hemodialysis related M-MDSC. Plasma IFN-γ, TNF-α and IL-6 were elevated in hemodialysis patients compared with healthy control. M-MDSC level was positively related to IL-6 level among hemodialysis patients. The plasma of hemodialysis patients induced M-MDSCs significantly compared with plasma from health donors. Besides, IL-6 neutralizing antibody significantly abrogated the induction. Neutralizing antibody of IFN-γ and TNF-α partially decreased the generation of arginase of the induced M-MDSC.ConclusionsM-MDSCs were elevated in ESRD patients under hemodialysis, and they exhibited a strong association with the risk of cardiovascular and cerebrovascular diseases. Hemodialysis related M-MDSC presented enhanced recruitment to atherosclerotic lesions, promoted the migration of endothelial cells through exhaustion of local L-arginine.

The role of myeloid-derived suppressor cells in hematologic malignancies.

This article focuses on the immunosuppressive impact of myeloid-derived suppressor cells (MDSCs) and the potential clinical implications in hematological malignancies. MDSCs play a critical role in the regulation of the immune response in cancer. They inhibit activation of adaptive immune response and as a result foster the growth of the malignancy. Recent studies have shown that MDSCs serve as prognostic biomarkers and as targets for cancer immunotherapy. Preclinical and clinical studies have identified new approaches to deplete MDSC populations and inhibit MDSC function with combination immunomodulatory therapies including chemotherapeutic agents with immune checkpoint-directed treatment. A broad spectrum of publications indicate that direct targeting of MDSCs may abrogate their protumorigenic impact within the tumor microenvironment through activation of the adaptive immune response.

Clinical Impact of Myeloid-Derived Suppressor Cells, Lymphocyte Subsets, and Neutrophil-to-Lymphocyte Ratio in Patients with Colorectal Cancer

Clinical Impact of Myeloid-Derived Suppressor Cells, Lymphocyte Subsets, and Neutrophil-to-Lymphocyte Ratio in Patients with Colorectal Cancer

Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs

BackgroundSolid tumors produce proteins that can induce the accumulation of bone marrow-derived cells in various tissues, and these cells can enhance metastatic tumor growth by several mechanisms. 4T1 murine mammary tumors are known to produce granulocyte colony-stimulating factor (G-CSF) and increase the numbers of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) in tissues such as the spleen and lungs of tumor-bearing mice. While surgical resection of primary tumors decreases MDSC levels in the spleen, the longevity and impact of MDSCs and other immune cells in the lungs after tumor resection have been less studied.MethodsWe used mass cytometry time of flight (CyTOF) and flow cytometry to quantify MDSCs in the spleen, peripheral blood, and lungs of mice bearing orthotopic murine mammary tumors. We also tested the effect of primary tumor resection and/or gemcitabine treatment on the levels of MDSCs, other immune suppressor and effector cells, and metastatic tumor cells in the lungs.ResultsWe have found that, similar to mice with 4T1 tumors, mice bearing metastatic 4T07 tumors also exhibit accumulation of CD11b+Gr1+ MDSCs in the spleen and lungs, while tissues of mice with non-metastatic 67NR tumors do not contain MDSCs. Mice with orthotopically implanted 4T1 tumors have increased granulocytic (G-) MDSCs, monocytic (M-) MDSCs, macrophages, eosinophils, and NK cells in the lungs. Resection of primary 4T1 tumors decreases G-MDSCs, M-MDSCs, and macrophages in the lungs within 48 h, but significant numbers of functional immunosuppressive G-MDSCs persist in the lungs for 2 weeks after tumor resection, indicative of an environment that can promote metastatic tumor growth. The chemotherapeutic agent gemcitabine depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils in the lungs of 4T1 tumor-bearing mice, and we found that treating mice with gemcitabine after primary tumor resection decreases residual G-MDSCs in the lungs and decreases subsequent metastatic growth.ConclusionsOur data support the development of therapeutic strategies to target MDSCs and to monitor MDSC levels before and after primary tumor resection to enhance the effectiveness of immune-based therapies and improve the treatment of metastatic breast cancer in the clinic.

Different role of circulating myeloid-derived suppressor cells in patients with multiple myeloma undergoing autologous stem cell transplantation

BackgroundThe aim of this study is to evaluate the prognostic impact of myeloid-derived suppressor cells (MDSCs) in multiple myeloma (MM) in the context of autologous stem cell transplantation (ASCT).MethodsPeripheral blood samples were collected for measuring monocytic (M-) MDSCs (CD14posHLA-DRlow/neg) and early-stage (E-) MDSCs (LinnegHLA-DRnegCD33posCD11bpos) before and after ASCT. Clinical outcomes following ASCT differed according to the frequency of each MDSC phenotype.ResultsIn the pre-ASCT analyses, lower M-MDSCs (<median) but not E-MDSCs were associated with a longer time to progression (TTP), whereas both MDSC phenotypes post-ASCT did not have a role in TTP. Both MDSC phenotypes pre-ASCT but not post-ASCT similarly suppressed in vitro autologous T and natural killer T cell proliferation. Importantly, pre-ASCT M-MDSCs more strongly inhibited the in vitro cytotoxic effect of melphalan compared with pre-ASCT E-MDSCs. Transcriptome analysis of each isolated MDSC subtype showed that expression of osteoclastic differentiation factors, particularly colony-stimulating factor 1 receptor (CSF1R), was significantly increased in M-MDSCs pre-ASCT. Finally, blockade of CSF1R substantially recovered the melphalan-induced cytotoxicity reduced by pre-ASCT M-MDSCs.ConclusionsOur data demonstrate that pre-ASCT M-MDSCs are correlated with poor clinical outcomes after ASCT through reduced cytotoxicity of melphalan. We propose that targeting CSF1R on these cells may improve the results of ASCT in MM.

Myeloid-Derived Suppressor Cells Accumulate in Intestinal Transplant Patients and Suppress Anti-Donor T-Cell Responses to Donor Epithelial Stem Cells

Background and aims: Recent advances in immunosuppressive regimens have decreased rejection rates and improved intestinal transplant (ITx) recipient survival. The potential mechanisms underlying these improvements remain to be elucidated. Myeloid-derived suppressor cells (MDSCs) are potent immature myeloid cells capable of suppressing T cell responses. The impact of MDSCs on clinical transplant outcomes remains unknown. Methods: Thirty-eight ITx recipients were enrolled from January 2015 to December 2016. Thirty-four ITx recipients received induction therapy and all received maintenance steroids and FK506. Peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the intraepithelial and lamina propria compartments were isolated. MDSCs were identified by antibody-staining and flow cytometry as: CD33+CD11b+lineage-HLA-DR-/low cells with 3 subsets, CD14-CD15- (I-MDSC), CD14+CD15- (M-MDSC), and CD14-CD15+ (G-MDSC) and used to perform functional studies of the MDSCs. Results: The total numbers of MDSCs and each subset of MDSCs significantly increased in PBMCs after ITx when compared with pre-transplant levels. All MDSC subsets suppressed CD4 and CD8 T-cell responses to anti-CD3 or allogenic B cell stimulation. Total numbers of MDSCs in PBMCs from ITx recipients with acute cellular rejection (ACR) were significantly lower than those without ACR. The number of MDSCs positively correlated with serum IL-6 levels and the glucocorticoid administration index based on the relative potency, but not with serum TNF-a levels and trough levels of FK506. IL-6 and methylprednisolone dramatically enhanced the differentiation of bone marrow cells to MDSC in vitro, suggesting steroid administration and IL-6 could induce accumulation of MDSCs after ITx. M-MDSCs and I-MDSCs expressed CCR1-3 but G-MDSCs expressed low/absent CCR1-3, and I-MDSCs and G-MDSCs but not M-MDSCs expressed CXCR2, suggesting MDSC have the potential to traffic to the intestinal grafts expressing the corresponding chemokine ligands. In support of this, the percentages of total MDSC and each subset among CD45+ cells in graft lamina propria mucosa significantly increased after ITx when compared with pre-reperfusion grafts. Finally, recipient MDSCs suppressed donor-reactive T cell-mediated destruction of ex vivo donor intestinal epithelial stem cell formation of organoids.FigureConclusion: These results indicate MDSC accumulation in ITx recipients and support their important role in controlling ACR.

Negative impact of myeloid-derived suppressor cells on CD8 effector T cell trafficking within the tumor microenvironment (TUM4P.924)

Abstract The success of immunotherapy and, unexpectedly, chemotherapy and radiation hinges on cytotoxic T cells gaining access to tumor targets. These observations have prompted interest in developing strategies to improve T cell trafficking in tumors. Here, we report that the ability of tumor vessels to respond to IL-6-dependent preconditioning regimens that boost CD8 effector T cell homing is temporally and inversely related to the expansion of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment. Using real-time intravital imaging and immunofluorescence histology, IL-6 therapies were shown to convert vessels from T cell-low to -high recruitment sites in murine tumors with minimal MDSC infiltration (i.e., CT26 colorectal, B16 melanoma, EMT6 mammary tumors). This conversion requires induction of the ICAM-1 trafficking molecule on tumor vessels. Conversely, mammary (4T1, AT-3 and PyMT-MMTV) and pancreatic (Pan02) tumors with high MDSC burdens were refractory to IL-6 therapies, but became responsive after acute MDSC depletion. To further investigate contributions of MDSC to poor trafficking, IL-6-responsive tumors were admixed at a ratio of 2:1 with MDSC from tumor-bearing mice. Sustained elevation of MDSC in admixed tumors resulted in failure to support increased T cell trafficking in response to IL-6-dependent therapy. Taken together, these findings identify a novel role for MDSC in immune evasion by limiting T cell trafficking at tumor vascular loci.

Impact of myeloid-derived suppressor cells on adoptive immunity in autoimmune arthritis (THER5P.827)

Abstract Abnormal B- and T-cell recognition of self-antigens and autoantibody production result in autoimmunity. We previously showed that myeloid-derived suppressor cells (MDSCs) suppress T cell proliferation in autoimmune arthritis. To further explore the impact of MDSCs on B cells, we examined B cell functions in vitro and in vivo in collagen-induced arthritis. We found the proliferation of collagen-primed B cells was inhibited by autologous monocytic MDSCs, but not by Ly6G+ neutrophils. The production of both IgG and IgM was reduced in the supernatant of B cell and monocytic MDSC co-cultures as compared to the supernatant from B cells alone or the supernatant from B cell-Ly6G+ cell co-cultures. Mechanistically, the levels of iNOS and PGE2 increased in the B cell-MDSC co-cultures, and addition of either iNOS or PGE2 inhibitors abolished the MDSC suppression of B cell proliferation. While neutralizing IL-12 also reestablished B cell proliferation, blockade of IL-6 and TNFa did not show similar effect. Finally, adoptive transfer of monocytic MDSCs to collagen-immunized mice resulted in reduced autoantibody production and mitigated arthritis severity. In summary our data show that monocytic MDSCs suppress autoreactive B cell proliferation and antibody production. The suppressive function requires iNOS, PGE2 and IL-12, but is independent of IL-6 and TNFa. These MDSCs can potentially be used in cell-based therapy to treat autoimmune arthritis by limiting B cell functions.

Myeloid derived suppressor cells are expanded in patients with multiple myeloma, induce Treg cells and delay T-cell recovery post transplantation

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of cells expressing immature myeloid markers and have been implicated as inhibitors of lymphopoiesis. We determined the number of MDSC in patients with multiple myeloma (MM), the impact of G-CSF on MDSC prior to stem cell collection, the ability of MDSC to induce Treg cells and the impact of MDSC on lymphocyte regeneration post-transplant.

Dynamic Change and Impact of Myeloid-Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells composed of hematopoietic progenitor cells, immature macrophages, dendritic cells, and granulocytes, which accumulate in inflammatory diseases and various cancers. Here, we investigated the dynamic changes and effects of MDSCs in graft-versus-host disease (GVHD) development and/or tumor relapse after syngeneic and allogeneic bone marrow transplantation (BMT). We found that adding functional MDSCs in donor graft alleviated GVHD, whereas removal of MDSCs in vivo exacerbated GVHD. After T cell-deplete BMT, MDSCs transiently accumulated in the blood and spleen of recipients without GVHD. In contrast, after T cell-replete BMT, the levels of blood MDSCs were constantly elevated in recipients with GVHD. MDSC accumulation positively correlated with the severity of GVHD. Additionally, MDSC accumulation was further increased upon tumor relapse. Although MDSCs isolated from both syngeneic and allogeneic BMT recipients inhibited T cell proliferation in response to alloantigen stimulation ex vivo, MDSCs from the recipients with GVHD showed much higher suppressive potency compared with those from recipients without GVHD. These results indicate that MDSCs can regulate the immune response in acute GVHD, and possibly tumor relapse, subsequent to allogeneic BMT.

Transplant Tolerance and Myeloid Supressor Cells

The successful organ transplantation is currently dependent on chronic administration of immunosuppressive drugs to non-specifically suppress immune response, causing severe side effects, including infection and cancer. Induction of specific tolerance is ideal solution, which, indeed, naturally occurs. Thus, ˜1/4 liver transplants in farm pigs were spontaneously accepted, inducing systemic specific tolerance. In humans, weaning off, leading to complete stop of immunosuppressive has achieved in ˜1/4 liver transplant patients. The underlying mechanisms remain unclear. We have investigated mouse liver transplant tolerance, and noted that, different from liver transplants that are spontaneously accepted, hepatocyte transplants are acutely rejected, suggesting immune regulatory activity of liver non-parenchymal cells. Hepatic stellate cells (HSC) turn out to be potent immunosuppressors. Cotransplantation with HSC effectively protects islet allografts from rejection. We demonstrated in this study that, in contrast to myeloid (CD11b+) cells in islet alone grafts that were CD11c+, CD11b+ cells in HSC/islet grafts expressed low CD11c and costimulatory molecules, but high arginase 1 and iNOS, and markedly inhibited T cell response - sharing many properties with myeloid derived suppressor cells (MDSC). MDSCconsisting of heterogeneous cell populations were initially identified in cancer patients contributing to immune evasion. The impact of MDSC on transplant tolerance has not been extensively studied. MDSC. Induction of MDSC by cotransplantation with HSC was dependent on IFN-g stimulation since HSC deficient in IFN-gR1 largely lost the ability to induce MDSC, and failed to protect islet allografts. The induction of MDSC by HSC was also confirmed by addition of HSC into BM-derived DC culture. The harvested floating cells were predominantly CD11b+CD11c− (not CD11c+), expressed high arginase 1 and iNOS, but low CD40, CD80 and CD86. They expressed Gr-1, F4/80, Ly6C, suggesting heterogeneous nature. Transwell culture data suggested that induction of MDSC by HSC was mediated by soluble factors. They demonstrated potent inhibitory activity against T cell response. Cotransplantation with in vitro-generated MDSC achieved long-term survival in 64% islets allografts as effective as cotransplantation with HSC, associated with reduction of graft CD8 T cells via apoptosis (annexin V), and expansion of antigen-specific Treg cells, which was mediated by B7-H1 expressed on MDSC since the MDSC generated from mice deficient in B7-H1 expression markedly reduced their ability to protect the cotransplanted islet allografts due to failure to induce sufficient Treg cells. In conclusion, MDSC play a crucial role in induction of transplant tolerance. IFN-γ/B7-H1 pathway appears to be crucial in establishing peripheral tolerance. Large amounts of MDSC can be generated in vitro, and can potentially be used for induction of transplant tolerance.