scholarly journals A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2254-2265 ◽  
Author(s):  
Samantha Solito ◽  
Erika Falisi ◽  
Claudia Marcela Diaz-Montero ◽  
Andrea Doni ◽  
Laura Pinton ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Myeloid Cells ◽  
Cell Subset ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Gm Csf ◽  
Immature Myeloid Cells ◽  
Rapid Generation ◽  
Worse Prognosis

Abstract We recently demonstrated that human BM cells can be treated in vitro with defined growth factors to induce the rapid generation of myeloid-derived suppressor cells (MDSCs), hereafter defined as BM-MDSCs. Indeed, combination of G-CSF + GM-CSF led to the development of a heterogeneous mixture of immature myeloid cells ranging from myeloblasts to band cells that were able to suppress alloantigen- and mitogen-stimulated T lymphocytes. Here, we further investigate the mechanism of suppression and define the cell subset that is fully responsible for BM-MDSC–mediated immune suppression. This population, which displays the structure and markers of promyelocytes, is however distinct from physiologic promyelocytes that, instead, are devoid of immuosuppressive function. In addition, we demonstrate that promyelocyte-like cells proliferate in the presence of activated lymphocytes and that, when these cells exert suppressive activity, they do not differentiate but rather maintain their immature phenotype. Finally, we show that promyelocyte-like BM-MDSCs are equivalent to MDSCs present in the blood of patients with breast cancer and patients with colorectal cancer and that increased circulating levels of these immunosuppressive myeloid cells correlate with worse prognosis and radiographic progression.

Interferon-γ-Induced Myeloid-Derived Suppressor Cells Aggravate Kidney Ischemia-Reperfusion Injury by Regulating Innate Immune Cells

Nephron ◽  
2021 ◽  
pp. 1-11
Author(s):  
Jiawei Ji ◽  
Yuan Zhuang ◽  
Zhemin Lin ◽  
Yihang Jiang ◽  
Wei Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Adoptive Transfer ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Gm Csf ◽  
Ifn Γ ◽  
Cell Functionality

<b><i>Objective:</i></b> Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context. <b><i>Methods:</i></b> The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice. <b><i>Results:</i></b> MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro<i>.</i> The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b<sup>+</sup>Ly6G<sup>−</sup>Ly6C<sup>high</sup> monocytic-MDSC phenotype decreased, whereas cells with a CD11b<sup>+</sup>Ly6G<sup>+</sup>Ly6C<sup>low</sup> polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4<sup>+</sup> and CD8<sup>+</sup> T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice. <b><i>Conclusions:</i></b> Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.

Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer

Blood ◽  
2013 ◽  
Vol 121 (10) ◽  
pp. 1740-1748 ◽  
Author(s):  
Karin Schmidt ◽  
Serena Zilio ◽  
Jan C. Schmollinger ◽  
Vincenzo Bronte ◽  
Thomas Blankenstein ◽  
...  
Keyword(s):  
Myeloid Cells ◽  
Antitumor Response ◽  
Gm Csf ◽  
Key Points ◽  
A Cell ◽  
Immature Myeloid Cells

Key Points iMC expand independent of the type of antitumor response and are not immunosuppressive in a cell-autonomous fashion iMC are licensed to become MDSC in vivo in the presence of GM-CSF

Myeloid-Derived Suppressor Cells Increase in Chronic Myeloid Leukemia and Exert Immune Suppressive Activity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2779-2779
Author(s):  
Cesarina Giallongo ◽  
Nunziatina Parrinello ◽  
Daniele Tibullo ◽  
Piera La Cava ◽  
Alessandra Cupri ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Enzymatic Activity ◽  
Myeloid Leukemia ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1

Abstract Abstract 2779 Background: Tumor cells are able to develop immune evasion mechanisms which induce a state of immune tolerance and inactivate tumor-specific T cells. In this context, in some solid tumors it has been demonstrated that a subpopulation of myeloid cells, defined as “myeloid-derived suppressor cells” (MDSCs), plays an important role in inducing T cell tolerance by production of arginase that depletes microenvironment of arginine, an essential aminoacid for T cell function. Since chronic myeloid leukemia (CML) patients have high levels of immature myeloid cells it is of interest to investigate if these cells have MDSCs phenotype and activity. Aim: The aim of this study was to analyze MDSCs and investigate their involvement in T-cell anergy of CML patients. Methods: MDSCs were analyzed in peripheral blood (PB) of 13 CML patients (at diagnosis and during therapy) and healthy donors (HD; n=20) by cytofluorimetric analysis (CD14+DR- for monocytic MDSCs and CD11b+CD33+CD14-DR- for granulocytic MDSCs). Arginase 1 expression was assessed in PB of HD and CML patient using real time PCR. Purification of granulocytes, monocytes and lymphocytes from PB was performed by a positive magnetic separation kit (EasySep, STEMCELL Technologies). Arginase activity was measured in granulocyte lysates using a colorimetric test after enzymatic activation and arginine hydrolysis. To evaluate the activation of CD3+ T lymphocytes after incubation with phytoemagglutinin, we analyzed at 24, 48, 72 h the following markers: CD69+, CD71+, DR+. Microvesicles were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. Results: CML patients showed high levels of monocytic and granulocytic MDSCs at diagnosis in comparison to HD (63±8 and 83±12,2% respectively in CML vs 4,9±2,1 and 55,8±5,3% respectively in HD; p<0.001) while after 3–6 months of tyrosine kinase inhibitors (TKIs) therapy MDSC levels returned to normal values. Either in PB and in the purified granulocytes subpopulation, arginase1 expression showed a 30 fold increase in CML at diagnosis (CML vs HD: p<0.01) and decreased after therapy. We also evaluated arginase enzymatic activity in granulocytes and we found it increased in CML patients (n=4) compared to HD (n=5) (p<0.05). CML as well as HD T lymphocytes showed a normal activation in vitro which was significantly lost when they was incubated with CML serum (n=4). In addition, an increase of monocytic MDSCs in vitro was observed after incubation of HD monocytes with CML serum (39±6%; p<0.01) or microvescicles (9,2±1,2%; p<0.05) compared to control serum. Conclusions: Granulocytic and monocytic MDSCs are increased in CML patients at diagnosis and decrease during TKIs treatment. Their levels also correlates with Arginase 1 expression and enzymatic activity in granulocytes. CML serum as well as CML microvesicles increase the percentage of HD monocytic MDSCs. Moreover, CML serum leads to anergy of T lymphocytes, probably by Arginase 1 secretion. Disclosures: Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

scholarly journals Myeloid-Derived Suppressor Cells (MDSCs) in Haematology

2021 ◽  
Vol 11 (1) ◽  
pp. 187
Author(s):  
Nikoleta Bizymi ◽  
Helen A. Papadaki
Keyword(s):  
T Cell ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses ◽  
Immature Myeloid Cells

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunomodulating properties, mainly acting by suppressing T-cell responses [...]

scholarly journals Myeloid-Derived Suppressor Cells Therapy Enhance Immunoregulatory Properties in Acute Graft Versus Host Diseas with Combination of Regulatory T Cells

2020 ◽  
Author(s):  
Min-Jung Park ◽  
Jin-Ah Baek ◽  
Se-Young Kim ◽  
Kyung-Ah Jung ◽  
Jeong Won Choi ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
B Cell ◽  
Immune Tolerance ◽  
Cell Subset ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Background: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and suppressing autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute Graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. Methods: We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for aGVHD following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysisResults: We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3+Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset.Conclusions: Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.

Myeloid Derived Suppressor Cells (MDSCs) Are Increased and Exert Immunosuppressive Activity In CML Patients At Diagnosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2711-2711
Author(s):  
Cesarina Giallongo ◽  
Nunziatina Parrinello ◽  
Daniele Tibullo ◽  
Piera La Cava ◽  
Alessandra Romano ◽  
...  
Keyword(s):  
T Cell ◽  
Western Blot ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Immunosuppressive Activity ◽  
Arginase 1

Abstract Introduction In some solid tumors it has been demonstrated that a subpopulation of myeloid cells, defined as “myeloid-derived suppressor cells” (MDSCs), plays an important role in inducing T cell tolerance by production of arginase 1 (arg1) that depletes microenvironment of arginine, an essential aminoacid for T cell function. Since chronic myeloid leukemia (CML) patients have high levels of immature myeloid cells it is of interest to investigate if these cells have MDSCs phenotype and activity. The aim of this study was to analyze MDSCs and investigate their activity in CML patients. Methods MDSCs were analyzed in peripheral blood (PB) of 20 healthy donors (HD) and 30 CML patients at diagnosis. In 21 patients MDSCs were also measured during TKI treatment. Granulocytic MDSCs (G-MDSCs) were identified as CD11b+CD33+CD14-HLADR- cells, while the monocytic MDSCs (Mo-MDSCs) as CD14+HLADR by cytofluorimetric analysis. Arg1 expression was assessed using real time PCR and Western Blot. Arg activity was measured in granulocyte lysates using a colorimetric test after enzymatic activation and arginine hydrolysis. Microvesicles (MV) were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. Results CML patients showed high levels of Mo- and G-MDSCs at diagnosis in comparison to HD (41±8 and 82,5±12,2% respectively for CML vs 9±2,1 and 55±5,3% for HD; p<0.001), while after TKIs therapy both subpopulations decreased, returning to normal values. T-reg (CD4+ CD25high Foxp3+ cells) were also significantly increased in CML patients at diagnosis in respect to HD (9±2% vs 6,1±0,8%, p<0.001) with a significant correlation with the percentage of Gr-MDSCs (r=0,6254; p<0.001). Both in PB and purified granulocytic cells, Arg1 expression showed a 30 fold increase in CML at diagnosis compared to HD (p<0.001) and decreased after therapy. The same data were confirmed by Western Blot analysis. Arg enzymatic activity in granulocytes resulted also increased in CML (n=10) compared to HD (n=10) (p<0.001). The suppressive function of CML G-MDSCs was demonstrated by their ability to inhibit the proliferation of CFSE+ HD T cells (p<0.001). In addition, an increase of Mo-MDSCs in vitro was observed after incubation of HD monocytes with CML sera (29±13%; p<0.0001) or MV (8±2,8%; p<0.05). Conclusions MDSCs are increased in CML patients at diagnosis and decrease during TKIs treatment. CML granulocytes have high arg1 activity and immunosuppressive activity. Moreover, CML serum as well as CML microvesicles increase the percentage of HD Mo-MDSCs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals GM-CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cells in vitro

2016 ◽  
Vol 5 (12) ◽  
pp. e119 ◽  
Author(s):  
Tessa Gargett ◽  
Susan N Christo ◽  
Timothy R Hercus ◽  
Nazim Abbas ◽  
Nimit Singhal ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Chemotherapeutic Agents ◽  
Myeloid Derived Suppressor Cells ◽  
Gm Csf

scholarly journals Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host disease with combination of regulatory T cells

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Min-Jung Park ◽  
Jin-Ah Baek ◽  
Se-Young Kim ◽  
Kyung-Ah Jung ◽  
Jeong Won Choi ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Immune Tolerance ◽  
Graft Versus Host Disease ◽  
Cell Subset ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Background Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. Methods We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysis. Results We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3 + Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset. Conclusions Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.

scholarly journals Myeloid-derived suppressor cells as a target for anticancer therapy

2018 ◽  
Vol 72 ◽  
pp. 1179-1198
Author(s):  
Natalia Anger ◽  
Joanna Rossowska
Keyword(s):  
Myeloid Cells ◽  
Suppressor Cells ◽  
Immune Checkpoints ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressor Activity ◽  
Premetastatic Niche ◽  
Current State ◽  
Tumor Diagnostics ◽  
Promote Tumor Growth ◽  
Immature Myeloid Cells

Myeloid-derived suppressor cells are heterogenic immature myeloid cells, which possess suppressor activity and play an important role in both, tumor progression and metastasis. The accumulation of MDSCs is induced primarily by factors that are secreted by the tumor microenvironment, which disturb myelopoiesis that occurs in the bone marrow and enables the migration of immature myeloid cells into the tumor. MDSCs promote tumor growth by inhibiting the activity of immunocompetent cells, as well as by activating non-immunological processes, such as tumor angiogenesis, the degradation of extracellular matrix and the formation of premetastatic niche. Due to their significant impact on the development of cancer, MDSCs became clinically relevant in tumor diagnostics. In recent years, various therapeutic strategies were developed in order to inhibit the proliferation, accumulation or suppressor activity of MDSCs, as well as to render the differentiation or total depletion of these cells. The proposed therapies often combine factors that reduce MDSCs suppression with conventional chemotherapy or with immune checkpoints inhibitors. In this review, we describe the current state of knowledge about factors that enable the accumulation of MDSCs, methods of phenotypic identification of these cells, as well as the mechanisms of suppression used by them. Moreover, we provide insight into the therapeutic approaches, which aim to restore the reactivity of the immune system by reducing the suppressor effects of MDSCs.

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