Role Of Myeloid-derived Suppressor Cells Research Articles

Abstract 6864: Tumor suppressor function of the ubiquitin ligase Siah1a in melanoma is mediated by myeloid derived suppressor cells

Abstract Growing evidence supports the important role of myeloid-derived suppressor cells (MDSC) in melanoma progression and response to therapy. MDSC contributes to a pro-tumorigenic phenotype, yet the mechanistic basis for the immune suppressor properties acquired by MDSC remains largely unknown. Mammals have two homologous Siah genes, Siah1 (Siah1a and Siah1b in mice) and Siah2. In the context of melanoma, the ubiquitin ligases Siah1a and Siah2 have melanoma-intrinsic and -extrinsic (immune) functions. Correspondingly, ablation of Siah1a/2 in melanoma or its microenvironment attenuates melanoma development in a number of mouse melanoma models. Given that number of macrophage clusters infiltrated into melanoma when grown in Siah2 KO mice, we set to assess macrophage function in melanoma. Selective ablation of Siah1a or Siah2 in macrophages, using Lyz2Cre, revealed that Siah1a but not Siah2 elicits a tumor suppressor function in melanoma. Inoculation of mouse melanoma Yummer1.7 cells (Braf mutated and Pten deleted) in mice lacking Siah1a in macrophages, resulted in bigger melanoma tumors compared to melanoma grown in either WT or mice in which macrophages were ablated of Siah2. FACS analysis of melanoma tumors grown in mice harboring Siah1a mutant macrophages revealed a significant increase in MDSC, which coincided with a decrease in CD4+ and CD8+ cells, compared with WT mice. These observations suggest that a lack of Siah1a in macrophages leads to an expansion of MDSC that affects surrounding immune cells, including T cells. RNA-seq analysis of MDSC that were differentiated in vitro from bone marrow cells of WT or Siah1a ablated macrophage mice revealed increased expression of genes involved in proliferation and alternative macrophage activation in MDSC lacking Siah1a when compared to the WT genotype. Mapping mechanisms underlying Siah1a tumor suppressor function is expected to reveal novel regulatory cues in melanoma control by the MDSC population while mapping novel means for stratifications of melanoma to therapy, and possibly new means for therapy of this tumor type. Citation Format: Marzia Scortegagna, Yuanning Du, Yongmei Feng, Ze'ev Ronai. Tumor suppressor function of the ubiquitin ligase Siah1a in melanoma is mediated by myeloid derived suppressor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6864.

Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy, and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. We enrolled recipients receiving orthotopic liver transplantation (OLT) and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, two cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In mice model, liver IRI mobilized MDSCs and promoted their infiltration in damaged liver, and intrahepatic MDSCs possessed with enhanced immunosuppressive function by up-regulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that CXCL17 was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs via binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated YAP/TEAD1 complex to promote CXCL17 transcription. Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of a therapeutic potential for managing IRI in liver surgery.

Pivotal role of myeloid-derived suppressor cells in infection-related tumor growth.

In this study, we investigated infection-related tumor growth, focusing on myeloid-derived suppressor cells (MDSCs) in clinical and experimental settings. In the clinical study, a total 109 patients who underwent gastrectomy or esophagectomy were included. Blood samples were collected from a preoperative time point through 3 months after surgery, and MDSCs were analyzed using flow cytometry. In animal experiments, peritonitis model mice were created by CLP method. We investigated the number of splenic MDSCs in these mice using flow cytometry. Malignant melanoma cells (B16F10) were inoculated on the back of the mice, and tumor growth was monitored. We compared the level of MDSC infiltration around the tumor and the migration ability between CLP and sham-operated mice-derived MDSCs. Finally, we focused on PD-L1+ MDSCs to examine the effectiveness of anti-PD-L1 antibodies on tumor growth in CLP mice. In patients with postoperative infectious complication, MDSC number was found to remain elevated 3 months after surgery, when the inflammatory responses were normalized. CLP mice showed increased numbers of MDSCs, and following inoculation with B16F10 cells, this higher number of MDSCs was associated with significant tumor growth. CLP-mice-derived MDSCs had higher levels of accumulation around the tumor and had more enhanced migration ability. Finally, CLP mice had increased numbers of PD-L1+ MDSCs and showed more effective inhibition of tumor growth by anti-PD-L1 antibodies compared to sham-operated mice. Long-lasting enhanced MDSCs associated with infection may contribute to infection-related tumor progression.

The Roles of Myeloid-Derived Suppressor Cells in Liver Disease.

Liver disease-related mortality is a major cause of death worldwide. Hepatic innate and adaptive immune cells play diverse roles in liver homeostasis and disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells. MDSCs can be broadly divided into monocytic MDSCs and polymorphonuclear or granulocytic MDSCs, and they functionally interact with both liver parenchymal and nonparenchymal cells, such as hepatocytes and regulatory T cells, to impact liver disease progression. The infiltration and activation of MDSCs in liver disease can be regulated by inflammatory chemokines and cytokines, tumor-associated fibroblasts, epigenetic regulation factors, and gut microbiota during liver injury and cancer. Given the pivotal roles of MDSCs in advanced liver diseases, they can be targeted to treat primary and metastatic liver cancer, liver generation, alcoholic and nonalcoholic liver disease, and autoimmune hepatitis. Currently, several treatments such as the antioxidant and anti-inflammatory agent berberine are under preclinical and clinical investigation to evaluate their therapeutic efficacy on liver disease and their effect on MDSC infiltration and function. Phenotypic alteration of MDSCs in different liver diseases that are in a model-dependent manner and lack special markers for distinct MDSCs are challenges for targeting MDSCs to treat liver disease. Multi-omics study is an option to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment. In summary, MDSCs play important roles in the pathogenesis and progression of liver disease by regulating both intrahepatic innate and adaptive immune responses.

Sulforaphane activates CD8+ T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

BackgroundExtensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However,...

Role of myeloid-derived suppressor cells in chronic brucellosis.

Human brucellosis, a Brucella infection caused most common zoonosis in the world, remains a serious public health burden in China. Brucella chronic infection always causes immunosuppressive status and results in severe organ or tissue damages. The aim of this work was to study the role of the myeloid-derived suppressor cells (MDSCs) in human chronic brucellosis. Fifty cases of chronic brucellosis and 40 healthy individual controls were enrolled in this study. We analyzed the frequency and subsets of MDSCs in PBMC between the chronic brucellosis and healthy control groups by flow cytometry. Furthermore, we also measured the inflammatory-related cytokines in serum samples and the MDSCs inhibition ability to the proliferation of T cells in vitro. We found that the frequency of MDSCs in peripheral blood and the level of IL-6 and IL-10 Th2 cytokines and Arginase-1 were significantly increased in chronic brucellosis patients. In addition, we also found that the T cell function was suppressed in vitro by co-culturing with MDSCs from brucellosis patients. Our study described an increase of immunosuppressive MDSCs in peripheral blood of chronic brucellosis patients. These results contribute to the understanding of Brucella persistent infection, which may provide an insight for effective treatment of chronic brucellosis patients in clinical practice.

High Levels of Circulating Granulocytic Myeloid-Derived Suppressor Cells (G-MDSCs) Predict Failure of CD19-Targeting CAR-T Cell Therapy

Background The mechanisms of resistance to CAR-T cell therapy may depend on the physical and biological characteristics of the tumor itself, on CAR-T cells in terms of efficiency and fitness, or on the microenvironment. Myeloid-derived suppressor cells (MDSCs) play a crucial role in hematological tumors, promoting immunosuppression and tumor progression. Their presence hampers the anti-tumor immune response, posing challenges for effective therapeutic interventions. The predictive role of myeloid-derived suppressor cells (MDSCs) of monocytic and granulocytic origin (M-MDSCs and G-MDSCs, respectively) in the context of CAR-T cell therapy is largely unknown. Aim and methods Our aim was to quantify circulating M-MDSC and G-MDSC in patients (n=26) receiving approved CAR-T cell products for high-grade B cell lymphoma or acute lymphoblastic leukemia. Whole blood samples were collected at enrolment (time point 1), after leukapheresis (time point 2) and just after Cy/Flu lymphodepletion (time point 3). Stringent criteria for multicolour flow cytometry identification of M-MDSC (CD14/HLA-DR/CD124/CD11b/CD45 and light scattering) and G-MDSC (CD15/CD11b/CD66b/oxidized low-density lipoprotein receptor -1, LOX-1, /CD45 and light scattering) were used. Blood samples were examined immediately after collection to prevent artefactual G-MDSC changes. Results M-MDSC number, although very variable between patients, remained essentially constant from time point 1 to time point 3 in each individual (range 1.2-947 cells/ml at the latest time point) and was not associated with a higher risk of relapse. Conversely, G-MDSC number, which was extremely low at time points 1 and 2, markedly increased at time point 3 (range 1.5-85.5 cells/ml). According to our preliminary data, at time point 3, mean G-MDSC were 39.3, 44.5, and 12.3 cells/ml in tisacel, axi-cel and brexu-cel, respectively. Mean G-MDSC were significantly lower in patients treated to receive brexu-cel (Figure 1). Responses were evaluated one, three, and six months after receiving CAR-T cells infusion. As we aimed at finding if G-MDSC could predict prognosis, we set a cut-off value of 30 G-MDSC/ml at time-point 3 (immediately after the completion of lymphodepletion); overall, approximately 35% of the patients had G-MDSC >30/ml at that moment. Kaplan-Meier survival analysis revealed that G-MDSC >30/ml at time point 3 associated with a higher risk of relapse, with a PFS of 80% vs 10% six months after CAR-T infusion ( p= 0.0002) (Figure 1). The sudden appearance of G-MDSC following the lymphodepletion is likely to reflect emergency granulopoiesis that favors an increased release of G-MDSC to the bloodstream and may be ideally customized with a tailored lymphodepletion. Conclusion In conclusion, here we show that the high circulating levels of G-MDSC induced by the lymphodepletion are associated with a lack of response to CAR-T cell therapy, thus representing a promising predictive biomarker of CAR-T cell therapy efficacy and possibly a hypothetical point of intervention for ameliorating CAR-T efficacy.

Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells.

Reinforcement of the immune-regulatory pathway is a feasible strategy for prevention and therapy of allergic asthma. The short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are pleiotropic microbial fermentation products known to induce regulatory T (Treg) cells and exert an immune-regulatory effect. The cellular mechanism underlying SCFA immune regulation in asthma is not fully understood. We investigated the role of myeloid-derived suppressor cells (MDSCs) and Treg cells, the immune-regulatory cells of innate and adaptive origin, respectively, in SCFA-elicited protection against allergic airway inflammation. BALB/c mice were given SCFA-containing drinking water before being rendered asthmatic in response to ovalbumen. When indicated, mice were given a GR1-depleting antibody to investigate the function of MDSCs in allergic inflammation of the airways. MDSCs were sorted to examine their immunosuppressive function and interaction with T cells. The mice receiving SCFAs developed less severe asthma that was accompanied by expansion of PMN-MDSCs and Treg cells. Mice depleted of PMN-MDSCs exhibited aggravated asthma, and the protective effect of SCFAs was abrogated after PMN-MDSC depletion. SCFAs were able to directly induce T-cell differentiation toward Treg cells. Additionally, we found that PMN-MDSCs enhanced Treg cell expansion in a cell contact-dependent manner. Whilst membrane-bound TGF-β has been shown to induce Treg cell differentiation, we found that MDSCs upregulated surface expression of TGF-β after coculture with T-cells and that MDSC-induced Treg cell differentiation was partially inhibited by TGF-β blockage. Although previous studies revealed Treg cells as the effector mechanism of SCFA immune regulation, we found that SCFAs ameliorate allergic airway inflammation by relaying immune regulation, with sequential induction of PMN-MDSCs and Treg cells.

Intranasal EP4 agonist and arginase-1 therapy in a murine model of asthma

Research findings evermore suggest a crucial role of myeloid-derived suppressor cells (MDSCs) in chronic lung diseases including asthma. Previously, we showed that intravenous (IV) treatment with a prostaglandin E2 receptor 4 (EP4) agonist, L-902,688, promoted MDSC suppressive activity. IV therapy with L-902,688 and BCT-100, a human pegylated arginase-1, ameliorated lung inflammatory features in a murine model of asthma. Here, we further investigate the potential therapeutic approach by studying the local therapy effects on the lungs after intranasal (IN) application. Using a two-week model of house dust mite (HDM)-induced murine asthma, the effect of IN treatment with L-902,688 or BCT-100 on in vivo lung function, inflammatory features of asthma and MDSC generation and activation was studied. Our experiments demonstrated increased suppressive activity of pulmonary MDSCs after induction of allergic airway disease. IN treatment with L-902,688 and BCT-100 further enhanced the immunosuppressive activity of pulmonary MDSCs. Additionally, treatment with BCT-100 reduced pulmonary T cell numbers. Asthmatic mice that received IN L-902,688 showed improved in vivo lung function. In conclusion, our results underline the potential of modulating MDSCs systemically or locally as a future therapeutic option in airway inflammatory diseases such as asthma.

Role of myeloid-derived suppressor cells in prediction of the effectiveness of biologics in children with psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by increased proliferation of epidermal cells, impaired keratinization, and an inflammatory reaction in the dermis due to activation of T-lymphocytes and synthesis of proinflammatory cytokines. Pathophysiology of psoriasis is associated not only with activation of proinflammatory reactions, but also with decreased anti-inflammatory functions of immunosuppressive cells. It is known that Treg, Breg and MDSCs do not perform their classical homeostatic functions in psoriasis. In recent years, there have been more and more cases of developing resistance to ongoing therapy with genetically engineered biological drugs (GEBD) in childhood, requiring replacement or discontinuation of the drug. The aim of our work was to estimate the content of MDSCs subpopulations and their functional activity in the peripheral blood of children with psoriasis at different effectiveness of biotherapeutic drugs. We examined 110 children with psoriasis vulgaris before the appointment of biologics, at 16 and 52 weeks of therapy with adalimumab, etanercept and ustikinumab, aged 6 to 18 years. Сomparison group consisted of 34 healthy children. The effectiveness of therapy was assessed by the achievement of PASI 75 by one year of therapy. Contents of myeloid-derived suppressor cells (MDSCs) and their subpopulations, and the activity of arginase-1 were assessed by multicolor flow cytometry. An increased content of MDSCs was found in children with psoriasis against the comparison group (p = 0.000). Analysis of the effectiveness of biologics in children with psoriasis, according to PASI, showed a significant reduction in disease severity in the group of patients with good effect, both at week 16 of therapy (p = 0.000) and by one year (p = 0.017). In the group of patients with good effect of biological therapy, percentage of total MDSCs population was higher, both before start of treatment and by 52nd week of therapy (p 0.01). Children with psoriasis showed increased immunosuppressive function of MDSCs by arginase-1 activity versus the comparison group (p = 0.000). The arginase-1 activity in patients with psoriasis at the stage of disease regression (PASI 10) was significantly increased relative to children in progressive stage of psoriasis (PASI10; p = 0.001). Thus, the content of MDSCs and their suppressive activity in children with psoriasis is an informative efficiency predictor of the biological drugs. Fading of biotherapy effect after the induction course is accompanied by decreased number of MDSCs and their functional activity.

Decreased programmed cell death ligand 2-positive monocytic myeloid-derived suppressor cells and programmed cell death protein 1-positive T-regulatory cells in patients with type 2 diabetes: implications for immunopathogenesis.

The activation of immune cells plays a significant role in the progression of type 2 diabetes. This study aimed to investigate the potential role of myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (Tregs) in type 2 diabetes. A total of 61 patients diagnosed with type 2 diabetes were recruited. Clinical characteristics were reviewed and peripheral blood samples were collected. We calculated the percentage of different cells. Frequencies of MDSC subsets refered to the percentage of G-MDSCs (CD15+CD33+CD11b+CD14-HLA-DR-/low) in CD45 positive cells and the percentage of M-MDSCs (CD14+CD15-CD11b+CD33+HLA-DR-/low) in lymphocytes plus monocytes. Frequencies of programmed cell death ligand 1-positive granulocytic MDSCs (PD-L1+ G-MDSCs), programmed cell death ligand 2-positive monocytic MDSCs (PD-L2+ M-MDSCs), PD-L2+ G-MDSC, and programmed cell death protein 1-positive Tregs (PD-1+Tregs) were decreased in patients with type 2 diabetes. The frequency of PD-1+ Tregs was positively related to PD-L2+ M-MDSCs (r= 0.357, P = 0.009) and negatively related to HbA1c (r = -0.265, P = 0.042), fasting insulin level (r = -0.260, P = 0.047), and waist circumference (r = -0.373, P = 0.005). Decreased PD-L2+ M-MDSCs and PD-1+ Tregs may promote effector T cell activation, leading to chronic low-grade inflammation in type 2 diabetes. These findings highlight the contribution of MDSCs and Tregs to the immunopathogenesis of type 2 diabetes and suggest their potential as targets for new therapeutic approaches.

CD39+MDSC facilitates cisplatin resistance of ovarian cancer cells by affecting adenosine synthesis.

Chemoresistance is a major cause of relapse or death in ovarian cancer (OC) patients. New evidence suggests the crucial role of myeloid-derived suppressor cells (MDSCs) in mediating chemoresistance of cancer cells. We aimed to dissect the way MDSCs affect the cisplatin resistance phenotype of OC and the related mechanisms. MDSCs were isolated from the spleen of OC mice isograft. CCK-8 and colony formation assays revealed the effects of an MDSC-conditioned medium with dysregulated CD39 on the proliferation and cisplatin sensitivity of OC cells. Fluorescence assay was used to reveal the effects of MDSCs with dysregulated CD39 on adenosine triphosphate (ATP) hydrolysis and adenosine (ADO) synthesis. MDSCs with highly expressed CD39 could facilitate the proliferation and cisplatin resistance of OC cells, while MDSCs with downregulated CD39 caused the opposite results. In addition, MDSCs with upregulated CD39 could facilitate the hydrolysis of immunogenic ATP to immunosuppressive ADO, while the introduction of CD39 inhibitor could repress such hydrolysis of ATP and generation of ADO, thereby abating the proliferation and cisplatin resistance of OC cells. CD39+MDSC could promote the proliferation and cisplatin resistance of OC cells by generating high concentrations of ADO, which indicates that targeting CD39+MDSC might be a feasible way to improve cisplatin resistance in OC.

The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling

Paracoccidioidomycosis (PCM) is a systemic mycosis with a high incidence in Latin America. Prior studies have demonstrated the significance of the enzyme Indoleamine 2,3-dioxygenase (IDO-1) in the immune regulation of PCM as well as the vital role of myeloid-derived suppressor cells (MDSCs) in moderating PCM severity. Additionally, Dectin-1 and Toll-Like Receptors (TLRs) signaling in cancer, infection, and autoimmune diseases have been shown to impact MDSC-IDO-1+ activity. To expand our understanding of MDSCs and the role of IDO-1 and pattern recognition receptors (PRRs) signaling in PCM, we generated MDSCs in vitro and administered an IDO-1 inhibitor before challenging the cells with Paracoccidioides brasiliensis yeasts. By co-culturing MDSCs with lymphocytes, we assessed T-cell proliferation to examine the influence of IDO-1 on MDSC activity. Moreover, we utilized specific antibodies and MDSCs from Dectin-1, TLR4, and TLR2 knockout mice to evaluate the effect of these PRRs on IDO-1 production by MDSCs. We confirmed the importance of these in vitro findings by assessing MDSC-IDO-1+ in the lungs of mice following the fungal infection. Taken together, our data show that IDO-1 expression by MDSCs is crucial for the control of T-cell proliferation, and the production of this enzyme is partially dependent on Dectin-1, TLR2, and TLR4 signaling during murine PCM.

Recruitment of myeloid‑derived suppressor cells and regulatory T‑cells is associated with the occurrence of acute myocardial infarction.

The roles of myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs) in acute myocardial infarction (AMI) remain elusive. The present study aimed to analyze the proportions of the granulocytic and monocytic populations of MDSCs (G-MDSCs and M-MDSCs, respectively), and Tregs in the peripheral blood mononuclear cells (PBMCs) of patients with AMI. The present study recruited 34 patients with AMI and 37 healthy controls without clinical signs of myocardial ischemia. PBMCs were isolated from the peripheral blood samples of patients with AMI within 24 h following admission to the hospital and from those of the healthy controls during a physical examination. Two subsets of MDSCs, G-MDSCs (CD15+CD33+CD11b+CD14-HLA-DRlow) and M-MDSCs (CD14+CD15-CD11b+HLA-DRlow), and Tregs (CD3+CD4+CD25highCD127low T-cells) in the PBMCs derived from the patients with AMI and healthy controls were analyzed using flow cytometry. The effects of MDSCs derived from patients with AMI on naïve CD4+ T-cells were examined in the co-culture system. The results revealed that the proportions of G-MDSCs and M-MDSCs were higher in the peripheral blood of patients with AMI than in that of the healthy controls. The patients with AMI had significantly higher numbers of programmed death-ligand (PD-L)1- and PD-L2-positive G-MDSCs and M-MDSCs compared with the healthy controls (P<0.05). The MDSCs could acquire a granulocytic phenotype following AMI, and the G-MDSCs and M-MDSCs would be more likely to express PD-L2 and PD-L1, respectively. The ratios of Tregs to CD4+ T-cells and PD-1+ Tregs in the peripheral blood of patients with AMI were significantly higher than those in the healthy controls (P<0.05). The results of flow cytometry demonstrated an increase in the numbers of inducible Tregs in the co-culture system with the G-MDSCs derived from patients with AMI compared with the G-MDSCs derived from the healthy controls (P<0.01). On the whole, the findings presented herein demonstrate the accumulation of MDSCs, and the upregulation of PD-L1 and PD-L2 expression on the surface of MDSCs in patients with AMI. MDSCs can induce the expansion of Tregs by binding PD-1 on the surface of Tregs, thus playing a crucial role in AMI.

Th17/Treg balance is regulated by myeloid-derived suppressor cells in experimental autoimmune myocarditis.

Autoimmune myocarditis is caused by both innate and adaptive immune responses. Many studies have found that myeloid-derived suppressor cells (MDSCs) suppress T-cell responses and reduce immune tolerance, while MDSCs may serve as a key player in inflammatory responses and pathogenesis in variety of autoimmune diseases. However, research into the role of MDSCs in experimental autoimmune myocarditis (EAM) remains lacking. We discovered that the expansion of MDSCs in EAM was closely related to the severity of myocardial inflammation. At an early stage of EAM, both adoptive transfer (AT) and selective depletion of MDSCs could inhibit the expression of IL-17 in CD4+ cells and downregulate the Th17/Treg ratio, alleviating excessive inflammation of EAM myocarditis. In another experiment, in addition, MDSCs transferred after selective depletion could increase IL-17 and Foxp3 expressions in CD4+ cells, as well as the Th17/Treg ratio, contributing to the aggravation of myocardial inflammation. MDSCs promoted the Th17 cell induction under Th17-polarizing conditions in vitro but suppressed Treg expansion. These findings suggest that MDSCs play a plastic role in sustaining mild inflammation in EAM by shifting Th17/Treg balance.

Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) were found to gradually accumulate in the orthotopic esophageal cancer mouse model during tumor progression. Although the roles of MDSCs in promoting tumor growth and inhibiting immune response have been extensively explored, currently, there are still no effective means for targeting MDSCs clinically. The deficiency of specific markers of MDSCs was responsible for the limited strategy to eliminating in clinic. This study identified that GPR84 was exclusively overexpressed on MDSCs. It was further found that GPR84 was prominently expressed on MDSCs in clinical samples and tumor mouse models, which drives the immunosuppression on CD8+T cells by inhibiting PD-L1 degradation in lysosomes. Furthermore, G-CSF and GM-CSF were found to induce GPR84 expression through the STAT3/C/EBPβ signaling pathway. In addition, GPR84+MDSCs and PD-L1+MDSCs were highly accumulated in anti-PD-1 therapy-resistant patients with esophageal cancer, and high GPR84 signature risk was verified as a negative factor for the overall survival of patients with anti-PD-1 treatment. Finally, GPR84 antagonism combined with an anti-PD-1 antibody enhanced the antitumor responses. Therefore, targeting GPR84 enhanced anti-PD-1 efficacy in esophageal cancer and other malignant tumors. This combination therapy has the potential for tumor therapy in clinics.

HIF-1α targeted deletion in myeloid cells decreases MDSC accumulation and alters microbiome in neonatal mice.

The newborn's immune system is faced with the challenge of having to learn quickly to fight off infectious agents, but tolerating the colonization of the body surfaces with commensals without reacting with an excessive inflammatory response. Myeloid-derived suppressor cells (MDSC) are innate immune cells with suppressive activity on other immune cells that regulate fetal-maternal tolerance during pregnancy and control intestinal inflammation in neonates. Until now, nothing is known about the role of MDSC in microbiome establishment. One of the transcription factors regulating MDSC homeostasis is the hypoxia-inducible factor 1α (HIF-1α). We investigated the impact of HIF-1α on MDSC accumulation and microbiome establishment during the neonatal period in a mouse model with targeted deletion of HIF-1α in myeloid cells (Hif1a loxP/loxP LysMCre+). We show that in contrast to wildtype mice, where an extensive expansion of MDSC was observed, MDSC expansion in neonatal Hif1a loxP/loxP LysMCre+ mice was dramatically reduced both systemically and locally in the intestine. This was accompanied by an altered microbiome composition and intestinal T-cell homeostasis. Our results point toward a role of MDSC in inflammation regulation in the context of microbiome establishment and thus reveal a new aspect of the biological role of MDSC during the neonatal period.

Tim-3 regulates the immunosuppressive function of decidual MDSCs via the Fyn-STAT3-C/EBPβ pathway during Toxoplasma gondii infection.

Myeloid-derived suppressor cells (MDSCs) play a key role in maintaining maternal-fetal tolerance for a successful pregnancy, but the role of MDSCs in abnormal pregnancy caused by Toxoplasma gondii infection is unknown. Herein, we revealed a distinct mechanism by which T-cell immunoglobulin domain and mucin domain containing protein-3 (Tim-3), an immune checkpoint receptor that balances maternal-fetal tolerance during pregnancy, contributes to the immunosuppressive function of MDSCs during T. gondii infection. The expression of Tim-3 in decidual MDSCs was significantly downregulated following T. gondii infection. The proportion of monocytic MDSCs population, the inhibitory effect of MDSCs on T-cell proliferation, the levels of STAT3 phosphorylation, and the expression of functional molecules (Arg-1 and IL-10) in MDSCs were all decreased in T. gondii-infected pregnant Tim-3 gene knockout (Tim-3KO) mice compared with infected pregnant WT mice. After treatment with Tim-3-neutralizing Ab in vitro, the expression levels of Arg-1, IL-10, C/EBPβ, and p-STAT3 were decreased, the interaction between Fyn and Tim-3 or between Fyn and STAT3 was weakened, and the binding ability of C/EBPβ to the promoters of ARG1 and IL10 was decreased in human decidual MDSCs with T. gondii infection, while opposite results were observed following treatment with galectin-9 (a ligand for Tim-3). Inhibitors of Fyn and STAT3 also downregulated the expression of Arg-1 and IL-10 in decidual MDSCs and exacerbated adverse pregnancy outcomes caused by T. gondii infection in mice. Therefore, our studies discovered that the decrease of Tim-3 after T. gondii infection could downregulate the functional molecules of Arg-1 and IL-10 expression in decidual MDSCs through the Fyn-STAT3-C/EBPβ signaling pathway and weaken their immunosuppressive function, which eventually contribute to the development of adverse pregnancy outcomes.

At Once Friends and Foes

Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) disease. In chronic infections such as TB, consistent pro-inflammatory signalling promotes the generation of myeloid-derived suppressor cells (MDSCs). MDSCs are innate immune cells that are further divided into polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subtypes on the basis of their morphology. These cells exert immunosuppressive effects on other immune cell types, thereby protecting the integrity of the lung tissue from damage caused by dysregulated Mtb. However, this comes at the expense of containing the Mtb infection. MDSCs’ unique double-edged role makes them an attractive target for host-directed TB therapeutics. This review aims to summarize current knowledge on the role of MDSCs in TB.

Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells

Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.