Potential Of Myeloid-derived Suppressor Cells Research Articles

Myeloid-derived suppressor cells in pleural effusion as a diagnostic marker for early discrimination of pulmonary tuberculosis from pneumonia.

Tuberculous pleural effusion (TPE) stands as one of the primary forms of extrapulmonary tuberculosis (TB) and frequently manifests in regions with a high prevalence of TB, consequently being a notable cause of pleural effusion in such areas. However, the differentiation between TPE and parapneumonic pleural effusion (PPE) presents diagnostic complexities. This study aimed to evaluate the potential of myeloid-derived suppressor cells (MDSCs) in the pleural fluid as a potential diagnostic marker for distinguishing between TPE and PPE. Adult patients, aged 18 years or older, who presented to the emergency room of a tertiary referral hospital and received a first-time diagnosis of pleural effusion, were prospectively enrolled in the study. Various immune cell populations, including T cells, B cells, natural killer (NK) cells, and MDSCs, were analyzed in both pleural fluid and peripheral blood samples. In pleural fluid, the frequency of lymphocytes, including T, B, and NK cells, was notably higher in TPE compared to PPE. Conversely, the frequency of polymorphonuclear (PMN)-MDSCs was significantly higher in PPE. Notably, compared to traditional markers such as the neutrophil-to-lymphocyte ratio and adenosine deaminase level, the frequency of PMN-MDSCs emerged as a more effective discriminator between PPE and TPE. PMN-MDSCs demonstrated superior positive and negative predictive values and exhibited a higher area under the curve in the receiver operating characteristic curve analysis. PMN-MDSCs in pleural effusion increased the levels of reactive oxygen species and suppressed the production of interferon-gamma from T cells following nonspecific stimulation. These findings suggest that MDSC-mediated immune suppression may contribute to the pathology of both TPE and PPE. The frequency of PMN-MDSCs in pleural fluid is a clinically useful indicator for distinguishing between TPE and PPE.

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.

Triptolide inhibits the proinflammatory potential of myeloid-derived suppressor cells via reducing Arginase-1 in rheumatoid arthritis

Triptolide (TPT) is widely used in the treatment of rheumatoid arthritis (RA). However, its regulatory mechanisms are not fully understood. This study demonstrated that Myeloid-derived suppressor cells (MDSCs) were expanded in both RA patients and arthritic mice. The frequency of MDSCs was correlated with RA disease severity and T helper 17 (Th17) responses. MDSCs from RA patients promoted the polarization of Th17 cells in vitro, which could be substantially attenuated by blocking arginase-1 (Arg-1). TPT inhibited the differentiation of MDSCs, particularly the monocytic MDSCs (M-MDSCs) subsets, as well as the expression of Arg-1 in a dose dependent manner. Alongside, TPT treatment reduced the potential of MDSCs to promote the polarization of IL-17+ T cell in vitro. Consistently, TPT immunotherapy alleviated adjuvant-induced arthritis (AIA) in a mice model, and reduced the frequency of MDSCs, M-MDSCs and IL-17+ T cells simultaneously. The presented data suggest a pathogenic role of MDSCs in RA and may function as a novel and effective therapeutic target for TPT in RA.

215.1: Therapeutic potential of myeloid-derived suppressor cells in islet transplantation

215.1: Therapeutic potential of myeloid-derived suppressor cells in islet transplantation

Expression of Inhibitory Molecules (Arginase-1, IDO, and PD-L1) by Myeloid-Derived Suppressor Cells in Multiple Myeloma Patients in Remission.

We studied suppressor potential of myeloid-derived suppressor cells (MDSC) in multiple myeloma patients, including before and after mobilization of hematopoietic stem cells (HSC), by evaluating the expression of arginase-1 (Arg1), indolamine-2,3-dioxygenase (IDO), and PD-L1 in MDSC subsets. The study included 20 multiple myeloma patients in remission, 5 patients with progression, as well as 10 sex-and age-matched healthy donors. The expression of Arg1, IDO, and PD-L1 in circulating granulocytic MDSC (G-MDSC, Lin-HLA-DR-CD33+CD66b+), monocytic MDSC (M-MDSC, CD14+HLA-DRlow/-), and early-stage MDSC (E-MDSC, Lin-HLA-DR-CD33+CD66b-) was evaluated by flow cytometry. Multiple myeloma patients in remission were characterized by reduced expression of Arg1 in M-MDSC in comparison with donors. The expression of Arg1 in M-MDSC depended on the number of induction therapy lines performed and was significantly lower in patients who received ⩾2 lines and responded with remission. Patients with multiple myeloma progression (resistant to therapy) showed significantly increased expression of Arg1 and PD-L1 in M-MDSC, as well as increased expression of Arg1 in E-MDSC. After G-CSF-induced mobilization of HSC, the content of circulating Arg1-expressing M-MDSC increased significantly. Considering the presence of MDSC in apheresis products, MDSC suppressive activity is discussed as a factor affecting the outcomes of autologous HSC transplantation in multiple myeloma patients.

Abstract P4-04-01: β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells

Abstract Summary Nerve-driven chronic adrenergic stress can suppress anti-tumor immunity. However, details are still missing or poorly understood. Catecholamines (epinephrine, norepinephrine) released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type including myeloid derived suppressor cells (MDSCs). MDSCs are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in tumor growth, differentiation and metastasis. Recently, we have shown that β2 adrenergic receptor signaling activated by chronic stress increases the immunosuppressive function of MDSCs, but the precise mechanisms remain unresolved. Building upon our earlier work, we now have discovered that the beta-2 adrenergic receptor (β2-AR) stress pathway drives the immune suppressive activity of MDSCs through altering their metabolism. First, we found that the expression of surface β2-AR on MDSCs increases with tumor growth in 4T1 breast cancer model and patients with breast cancer. We also found that β2-AR signaling decreases glycolysis, while increasing oxidative phosphorylation and fatty acid oxidation (FAO). β2-AR signaling also increased mitochondrial intensity and mitochondrial potential of MDSCs both in vitro and in vivo. β2-AR signaling in MDSCs also increased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) necessary for the FAO-mediated immunosuppressive function of MDSCs. Blocking CPT1A using etomoxir decreased tumor growth and immunosuppressive function of MDSCs in Wild Type (WT) mice but not β2-AR-/- mice or severe combined immunodeficient mice (SCID) mice. Moreover, we found that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2 in both mouse MDSCs and. PBMCs derived MDSCs. Together, our data reveal that stress-driven β2-AR signaling is an important physiological determinant that regulates key metabolic pathways in MDSCs enabling their immunosuppressive function. These data reveal a major, physiologically relevant role for nervous activity and adrenergic stress in MDSC-tumor biology. Keywords: β2 adrenergic receptor, stress, MDSC, Metabolism, Breast Cancer, Citation Format: Hemn Mohammadpour. β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-01.

Age-related expansion and increased osteoclastogenic potential of myeloid-derived suppressor cells

Aging is associated with excessive bone loss that is not counteracted with the development of new bone. However, the mechanisms underlying age-related bone loss are not completely clear. Myeloid-derived suppressor cells (MDSCs) are a population of heterogenous immature myeloid cells with immunosuppressive functions that are known to stimulate tumor-induced bone lysis. In this study, we investigated the association of MDSCs and age-related bone loss in mice. Our results shown that aging increased the accumulation of MDSCs in the bone marrow and spleen, while in the meantime potentiated the osteoclastogenic activity of the CD11b+Ly6ChiLy6G+ monocytic subpopulation of MDSCs. In addition, CD11b+Ly6ChiLy6G+ MDSCs from old mice exhibited increased expression of c-fms compared to young mice, and were more sensitive to RANKL-induced osteoclast gene expression. On the other hand, old mice showed elevated production of IL-6 and receptor activator of nuclear factor kappa-B ligand (RANKL) in the circulation. Furthermore, IL-6 and RANKL were able to induce the proliferation of CD11b+Ly6ChiLy6G+ MDSCs and up-regulate c-fms expression. Moreover, CD11b+Ly6ChiLy6G+ MDSCs obtained from old mice showed increased antigen-specific T cell suppressive function, pStat3 expression, and cytokine production in response to inflammatory stimulation, compared to those cells obtained from young mice. Our findings suggest that CD11b+Ly6ChiLy6G+ MDSCs are a source of osteoclast precursors that together with the presence of persistent, low-grade inflammation, contribute to age-associated bone loss in mice.

Granulocyte Colony-Stimulating Factor Attenuates Renal Ischemia-Reperfusion Injury by Inducing Myeloid-Derived Suppressor Cells.

Granulocyte colony-stimulating factor (G-CSF) can increase populations of myeloid-derived suppressor cells, innate immune suppressors that play an immunoregulatory role in antitumor immunity. However, the roles of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury remain unclear. We used mouse models of ischemia-reperfusion injury to investigate whether G-CSF can attenuate renal injury by increasing infiltration of myeloid-derived suppressor cells into kidney tissue. G-CSF treatment before ischemia-reperfusion injury subsequently attenuated acute renal dysfunction, tissue injury, and tubular apoptosis. Additionally, G-CSF treatment suppressed renal infiltration of macrophages and T cells as well as renal levels of IL-6, MCP-1, IL-12, TNF-α, and IFN-γ, but it increased levels of IL-10, arginase-1, and reactive oxygen species. Moreover, administering G-CSF after ischemia-reperfusion injury improved the recovery of renal function and attenuated renal fibrosis on day 28. G-CSF treatment increased renal infiltration of myeloid-derived suppressor cells (F4/80-CD11b+Gr-1int), especially the granulocytic myeloid-derived suppressor cell population (CD11b+Ly6GintLy6Clow); splenic F4/80-CD11b+Gr-1+ cells sorted from G-CSF-treated mice displayed higher levels of arginase-1, IL-10, and reactive oxygen species relative to those from control mice. Furthermore, these splenic cells effectively suppressed in vitro T cell activation mainly through arginase-1 and reactive oxygen species, and their adoptive transfer attenuated renal injury. Combined treatment with anti-Gr-1 and G-CSF showed better renoprotective effects than G-CSF alone, whereas preferential depletion of myeloid-derived suppressor cells by pep-G3 or gemcitabine abrogated the beneficial effects of G-CSF against renal injury. G-CSF induced renal myeloid-derived suppressor cells, thereby attenuating acute renal injury and chronic renal fibrosis after ischemia-reperfusion injury. These results suggest therapeutic potential of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury.

Abstract P3-01-02: B2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

Abstract Chronic stress is thought to suppress immunity; however, details about how chronic stress affects tumor growth and anti-tumor immune responses are still missing or poorly understood. Catecholamines (epinephrine, norepinephrine) released during sympathetic nerve stimulation can activate adrenergic receptors present on nearly every cell type including myeloid derived suppressor cells (MDSCs). MDSCs are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in promoting tumor growth, differentiation and metastasis. Here, we demonstrate that the chronic adrenergic stress (as manipulated by a) housing temperature (which affects norepinephrine (NE) production, b) use of b-AR agonists or antagonists, or c) using β2-AR knockout mice regulates the accumulation and the pro-tumor phenotype of MDSCs. This same result was seen using two different murine models of breast cancer (4T1 and AT-3) and through the use of β2-AR knockout mice, we found that these effects are dependent on β2-adrenergic receptor (β2-AR) signaling. Using an agonist of β-AR signaling, we found that the activation of β2-AR signaling increases the expression of immunosuppressive molecules such as arginase-I and PDL-1 in MDSCs and enhances their immune-regulatory functions. β2-AR expression in MDSCs was induced by tumor promoting cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The survival of MDSCs is increased upon the activation of β2-AR on MDSCs in a Fas-FasL dependent manner. The regulation by β-AR signaling on MDSCs is dependent upon phosphorylation of STAT3 as a pivotal transcription factor in the function and expansion of MDSCs while MDSCs lacking β2-AR had poorer survival in both spleen and tumor. In murine tumor models, we found that the tumor promoting effects of β2-AR activation can be prevented by simple treatment of mice with β-blockers or by peripheral sympathectomy using 6-hydroxydopamine (6-OHDA). Furthermore, treatment with β-AR agonist increases the generation and immunosuppressive functions of MDSCs derived from human PBMCs in vitro. These data reveal a major, physiologically relevant role for nervous activity and adrenergic stress in MDSC-tumor biology and underscore the clinical potential for blockade of a previously unrecognized β2-AR-MDSC axis to improve immunotherapy. Keywords: β2 adrenergic receptor, MDSC, Chronic Stress, Tumor, STAT3 Citation Format: Hemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, Elizabeth A. Repasky. B2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-02.

β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells.

Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (β2-AR-/-) mice, and adoptive transfer approaches, we found that the degree of β2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of β2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the β2-AR-mediated increase in MDSC survival is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses, which reveal a greater expression of apoptosis-related genes in β2-AR-/- MDSCs. Our data reveal the potential of β2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs can be mitigated by treatment with β-AR antagonists, or enhanced by β-AR agonists. This strongly supports the possibility that reducing stress-induced activation of β2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.

Therapeutic potential of monocytic MDSCs from peripheral blood monocytes in transplant rejection

Myeloid-derived suppressor cells (MDSCs) were initially found to contribute to immunosuppression in tumor patients and have recently been recognized as a subset of innate immune cells. They are a heterogeneous population composed of monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs). In addition, MDSCs have been reported to induce immunological tolerance and prolong the graft survival in transplantation. In mouse CD11b+ Gr-1+ cells, MDSCs have been reported to exhibit immunosuppressive functions under various inflammatory conditions. On the other hand, human MDSCs do not have a universal marker and have not been well defined. Furthermore, while mouse CD11b+ Gr-1+ MDSCs account for 20-30% of bone marrow cells, human peripheral blood includes only a few percent of MDSCs. Hence, further investigations of human MDSCs and the development of strategies for isolating human MDSCs are mandatory for their use in the clinic for transplantation. We previously established a new strategy to generate monocytic MDSCs in vitro and to isolate them from human peripheral blood mononuclear cells (PBMC). Based on these studies, we have concluded that they have great potential for suppressing cytotoxic T lymphocyte (CTL) – mediated xenocytotoxicity and NK-mediated xenocytotoxicity. Furthermore, they also suppress macrophage-mediated xenocytotoxicity significantly. Here, we review the therapeutic potential of MDSCs in transplantation.

Abstract A151: Radiation-induced TGFβ regulates the myeloid compartment to suppress antitumor immunity

Abstract One mechanism tumors use to evade immune responses is to regulate the abundance of myeloid-derived suppressor cells (MDSC), mainly through secreted factors (Gabrilovich and Nagaraj, 2009; Gabrilovich et al., 2012; Nagaraj and Gabrilovich, 2010). Here we examined whether this is affected by radiation therapy, which recent studies suggest can effectively prime anti-tumor immunity (Formenti and Demaria, 2012; Golden et al., 2012). In contrast, we have shown that radiation very efficiently activates TGFβ which is a suppressor of the adaptive immune response, particularly inhibiting T-cell activity and inducing T-regulatory cells. TGFβ also regulates innate immune response, particularly MDSC, which are a subset of immature myeloid precursors that are potent inhibitors of anti-tumor immunity. Here, we irradiated human breast cancer cell lines that were co-cultured with human monocytic precursors derived from circulating peripheral blood mononuclear cells (PBMC) isolated from healthy blood donors. CD14+ immature myeloid cells (IMC) stimulated with GM-CSF and IL-6 generated CD33+/CD11b+ MDSC with high efficiency (up to 90%). Consistent with the literature, TGFβ significantly promotes the accumulation of MDSC. IMC treated with TGFβ generated twice as many MDSC compared to the positive control of monocytes treated with alone (Mean = 18,509 -/+ 1523 cells (GM-CSF + IL-6 +TGFβ) vs 9010 -/+803.8 cells (GM-CSF + IL-6); N = 11 independent donors). Accordingly, small molecule TβRI inhibitor (LY 2109761) blocked this effect and further reduced by 50% the generation of MDSC compared to the GM-CSF and IL-6 positive control (Mean = 5371 -/+796.8 cells (GM-CSF + IL-6 + LY2109761 vs 9010 -/+803.8 cells (GM-CSF + IL-6); N = 11 independent donors). As reported (Lechner et al., 2010), tumor cell lines varied in their capacity to elicit MDSC from co-cultured IMC; being MCF7 less efficient than BT549, which are less efficient than MDA-MB-231. MDA-MB-231, which expresses higher levels of GM-CSF and IL-6 mRNA than the other cell lines, was used to test the effect of radiation. IMC were added to MDA-MB-231 monolayers irradiated with 5 Gy and co-cultured for 5 days in complete media (RPMI + 10% FBS). Tumor cell irradiation did not affect MDSC numbers but increased MDSC immunosuppressive capacity, as shown by a significant reduction in autologous CD8+ T-cell proliferation. This effect was TGFβ-dependent, as the immunosuppressive potential of MDSC was significantly reduced when they were generated in a context of TGFβ pathway inhibition. These results suggest that the combination of radiation therapy and inhibition of the TGFβ pathway may have a great therapeutic potential by releasing the suppressive action of MDSC on the anti-tumor immune responses. * This project has been funded through the Lilly Research Award Program (LRAP) Citation Format: Alba Gonzalez Junca, Ilenia Pellicciotta, Kyla Driscoll Carroll, David Schaer, Mary Helen Barcellos-Hoff. Radiation-induced TGFβ regulates the myeloid compartment to suppress antitumor immunity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A151.

MicroRNA-200c Promotes Suppressive Potential of Myeloid-Derived Suppressor Cells by Modulating PTEN and FOG2 Expression.

Myeloid-derived suppressor cells (MDSCs) constitute one of the major populations that potently suppress anti-tumor immune responses and favor tumor growth in tumor microenvironment. However, the mechanism(s) regulating the differentiation and suppressive function of tumor-associated MDSCs remain(s) unclear. Here, we identified a microRNA-200c (miR-200c), whose expression was dramatically induced by tumor-derived factors. Meanwhile, we also demonstrated that GM-CSF was a main inducer of miR-200c in tumor environment, and miR-200c in turn promoted the expansion and immune suppressive activity of MDSCs via targeting phosphatase and tensin homolog (PTEN) and friend of Gata 2 (FOG2), which can lead to STAT3 and PI3K/Akt activation. Finally, we examined in vivo suppressive function of miR-200c transfected MDSCs and found that miR-200c could remarkably promote tumor growth via modifying MDSCs. Thus, GM-CSF induced miR-200c in tumor environment plays a critical role in governing the expansion and functions of tumor-associated MDSCs and serves as a potential target in immunotherapy against tumor.

Both miR-17-5p and miR-20a Alleviate Suppressive Potential of Myeloid-Derived Suppressor Cells by Modulating STAT3 Expression

Myeloid-derived suppressor cells (MDSCs) were one of the major components of the immune suppressive network. STAT3 has an important role in regulating the suppressive potential of MDSCs. In this study, we found that the expression of STAT3 could be modulated by both miR-17-5p and miR-20a. The transfection of miR-17-5p or miR-20a remarkably reduces the expression of reactive oxygen species and the production of H(2)O(2), which are regulated by STAT3. MDSCs transfected with miR-17-5p or miR-20a are less able to suppress Ag-specific CD4 and CD8 T cells. Importantly, both miR-17-5p and miR-20a alleviate the suppressive function of MDSCs in vivo. The expression of miR-17-5p and miR-20a in tumor-associated MDSCs was found to be lower than in Gr1(+)CD11b(+) cells isolated from the spleens of disease-free mice. Tumor-associated factor downregulates the expression of both miR-17-5p and miR-20a. The modulation of miR-17-5p and miR-20a expression may be important for the process by which patients with a tumor can overcome the immune tolerance mediated by MDSCs. Our results suggest that miR-17-5p and miR-20a could potentially be used for immunotherapy against diseases, especially cancer, by blocking STAT3 expression.