Levels Of Myeloid-derived Suppressor Cells Research Articles

Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus–Induced Immunotolerance

Background & AimsThe immune tolerance induced by Hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV. MethodsWe utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including HBsAg, HBeAg, HBcAg, HBV DNA, and HBV RNA. ResultsOur study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (ManfMye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in ManfMye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in ManfMye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an HBsAg vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice. ConclusionThe current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/ STAT3 signaling, leading to MDSC-mediated CD8+ T cell exhaustion.

Hepatic recruitment of myeloid-derived suppressor cells upon liver injury promotes both liver regeneration and fibrosis

BackgroundThe liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury.MethodsWe established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-β were measured by ELISA assay and followed by being blocked with specific antibodies.ResultsThe intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G−Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-β. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs).ConclusionsThe dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.

Knock down of APE1 suppressed gastric cancer metastasis via improving immune disorders caused by myeloid-derived suppressor cells

ABSTRACT Gastric cancer is a highly immunogenic malignancy. Immune tolerance facilitated by myeloid-derived suppressor cells (MDSCs) has been implicated in gastric cancer resistance mechanisms. The potential role of APE1 in regulating gastric cancer metastasis by targeting MDSCs remains uncertain. In this study, the plasmid Plxpsp-mGM-CSF was used to induce high expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in GES-1 cells. For tumor transplantation experiments, AGS, AGS+GM-CSF and AGS+GM-CSF-siAPE1 cell lines were established by transfection, followed by subcutaneous implantation of tumor cells. MDSCs, Treg cells, IgG, CD3 and CD8 levels were assessed. Transfection with siAPE1 significantly inhibited tumor growth compared to the AGS+GM-CSF group. APE1 gene knockdown modulated the immune system in gastric cancer mice, characterized by a decrease in MDSCs and an increase in Treg cells, IgG, CD3 and CD8. In addition, APE1 gene knockdown resulted in decreased levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12). Furthermore, APE1 gene knockdown inhibited proliferation, migration and invasion of AGS and MKN45 cells. AGS-GM-CSF cell transplantation increased MDSC levels and accelerated tumor growth, whereas APE1 knockdown reduced MDSC levels, inhibited tumor growth and attenuated inflammatory infiltration in gastric cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach to the prevention and treatment of gastric cancer, providing new insights into its management.

Listeria-vectored cervical cancer vaccine candidate strains reduce MDSCs via the JAK-STAT signaling pathway.

Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.

SUPPRESSOR CELLS (MDSC) REGULATE THE T-CELL RESPONSE IN OLD MICE IMMUNIZED WITH THE WHOLE-VIRION SARS-CoV-2 VACCINE

Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive population involved in pathological processes associated with chronic inflammation. In recent years, the role of these cells in the regulation of a number of non-pathological processes, in particular, in the development of vaccine-induced immune response, has been actively discussed. This work was aimed at investigating the role of MDSC in the development of an immune response in old mice immunized with an inactivated whole virion SARS-CoV-2. Immunization of old animals induced an increase in the relative content of B cells and the production of specific antibodies to S1 and N proteins of SARS-CoV-2 in titers comparable to those of young animals. At the same time, elevated MDSC levels in aged animals negatively correlated with the level of CD8+ T cells. Splenic MDSCs in old animals were characterized by increased production of reactive oxygen species compared to young animals. In vitro experiments showed that MDSC depletion increased antigen-specific production of IFNγ by CD4+ T cells. The data obtained suggest a negative role for MDSC in regulating the T-cell vaccine-induced response to inactivated SARS-CoV-2 and encourage further studies in this direction, which may be a key to developing approaches to increase the efficacy of vaccines against SARS-CoV-2 in at-risk groups.

Evaluating Leukocyte Telomere Length and Myeloid-Derived Suppressor Cells as Biomarkers for Prostate Cancer.

Leukocyte telomere length (LTL) and myeloid-derived suppressor cells (MDSC) are associated with aging and the development and progression of cancer. However, the exact nature of this relationship remains unclear. Our study aimed to investigate the potential of LTL and MDSC as diagnostic biomarkers for prostate cancer while also seeking to deepen our understanding of the relationship of these potential biomarkers to each other. Our study involved patients undergoing a prostate biopsy. We analyzed the relative LTL in genomic DNA obtained from peripheral blood leukocytes as well as the percentage of MDSC and their subtypes in peripheral blood mononuclear cells (PBMC). Our evaluation focused on examining the relationship between LTL and MDSC and pathological diagnoses as well as investigating the correlation between LTL and MDSC levels. In our study of 102 participants, 56 were pathologically diagnosed with localized prostate cancer (cancer group), while 46 tested negative (control group). The cancer group exhibited significantly shorter LTL in comparison to the control group (p = 0.024). Additionally, the cancer group showed a tendency towards a higher percentage of monocytic MDSC (M-MDSC), although this difference did not reach statistical significance (p = 0.056). Our multivariate logistic regression analysis revealed that patients with shorter LTL and higher percentages of M-MDSC had a 2.98-fold (95% CI = 1.001-8.869, p = 0.049) and 3.03-fold (95% CI = 1.152-7.977, p = 0.025) increased risk of prostate cancer diagnosis, respectively. There was also a significant negative correlation between LTL and M-MDSC. (r = -0.347, p < 0.001). Our research has established a correlation between LTL and MDSC in patients undergoing biopsy for prostate cancer. Notably, we observed that individuals with localized prostate cancer tend to have shorter LTL and a higher percentage of M-MDSC prior to their diagnosis. These findings suggest that LTL and M-MDSC could potentially serve as adjunctive biomarkers for the early diagnosis of prostate cancer.

Abstract 1831: Reduction of PMN-MDSC level/activity following the consumption of white button mushroom in prostate cancer murine models and patients: A translational study to mitigate cancer progression

Abstract Frequent consumption of edible mushrooms, such as white button mushrooms (WBM), has been associated with a lower risk of prostate cancer [1]. Our laboratory at City of Hope has over 20 years of collective experience in defining the anticancer mechanisms of WBM [2, 3]. Previous studies have indicated that WBM consumption has anti-androgenic activities in prostate cancers in both preclinical models [4] and clinical trials [5]. In our first-in-human phase 1 trial on prostate cancer patients, we ensured the safety of consuming WBM in humans. In addition to observing a therapeutic-responsive decline in prostate-specific antigen (PSA), the levels of myeloid-derived suppressor cells (MDSCs) reduced in responders to WBM treatments [5]. These observations led us to hypothesize that WBM may mitigate the progression of prostate cancer in part by modulating the immune response. In the current study, we conducted translational research in syngeneic murine models and in prostate cancer patients from an ongoing phase 2 trial, aiming to define the immunomodulatory activity and mechanisms of WBM. We confirmed that WBM consumption in mouse models altered the number and function of immunosuppressive cells (MDSCs) and anti-tumor immune cells (T &amp; NK cells), ultimately enhancing the intratumor and systemic immune responses. At a bulk-transcriptional level, we observed the elevated expression of programmed cell death protein 1 (PD-1) in xenograft tumors. In our single immune cell profiling of patients’ blood specimens following 3 months of WBM consumption in freeze-dried tablets form, we investigated the transcriptional landscape of circulating immune cells in response to WBM interventions. The level of circulating neutrophil-associated PMN-MDSCs decreased, and the remaining cells showed transcriptional profiles associated with "neutrophil chemotaxis", "leukocyte aggregation", and "regulation of inflammatory response", as functions associated with enhanced anti-tumor activity. Lastly, we also showed in a mouse model that WBM consumption synergistically enhances the anticancer activity of anti-PD1 drugs, indicating that WBM may be used as adjuvant therapy with immune checkpoint inhibitors. In summary, our results from prostate cancer patients and murine models show the immunomodulatory effects of WBM consumption and provide a scientific foundation for the application of WBM in alleviating prostate cancer progression. References 1, Zhang S., et al. Int. J. Cancer. 2019; 146:2712-2720. 2, Chen S., et al. Cancer Res. 2006; 66:12026-12034. 3, Adams L.S., et al. Nutr. Cancer. 2008; 60:744-756. 4, Wang X., et al. J. Nutr. Biochem. 2021; 89:108580.5, Twardowski P., et al. Cancer. 2015; 121:2942-2950. Citation Format: Xiaoqiang Wang, Shoubao Ma, Przemyslaw Twardowski, Clayton Lau, Yin Chan, Kelly Wong, Jinhui Wang, Xiwei Wu, Paul Frankel, Timothy G. Wilson, Timothy W. Synold, Cary Presant, Jianhua Yu, Shiuan Chen. Reduction of PMN-MDSC level/activity following the consumption of white button mushroom in prostate cancer murine models and patients: A translational study to mitigate cancer progression [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 1831.

Myeloid derived suppressor cells in peripheral blood can be a prognostic factor in canine transitional cell carcinoma

Myeloid-derived suppressor cells (MDSCs) are immature cells with immunosuppressive properties found in the tumor microenvironment. MDSCs are divided into two major subsets: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). Both MDSC subsets contribute to the creation of an immunosuppressive environment for tumor progression. In humans, patients with high levels of MDSCs show worse outcomes for several types of cancers. However, the association between MDSCs and clinical features has rarely been investigated in canine studies. In the present study, we measured the proportion of PMN-MDSCs and M-MDSCs in the peripheral blood and tumor tissue of dogs with hepatocellular carcinoma (HCC), prostate cancer (PC), transitional cell carcinoma (TCC), lymphoma, and pulmonary adenocarcinoma. Additionally, we examined immunosuppressive ability of PMN-MDSCs and M-MDSCs in peripheral blood mononuclear cells of TCC case on CD4+, CD8+ and interferon-γ+ cells and investigated the relationships of MDSCs with clinical features and outcomes. PMN-MDSCs increased in HCC, PC, TCC, and lymphoma. In contrast, M-MDSCs increased in the TCC. Both PMN-MDSCs and M-MDSCs exhibited immunosuppressive effects on CD8+, CD4+ and interferon-γ+ cells. In dogs with TCC, lymph node metastasis was associated with high level of PMN-MDSCs but not with M-MDSCs. High levels of both PMN-MDSCs and M-MDSCs were related to advanced tumor stage. Kaplan-Meier analysis revealed that high levels of both PMN-MDSCs and M-MDSCs were significantly associated with shorter overall survival. In addition, the Cox proportional hazard regression model showed that M-MDSCs and the tumor stage were independent prognostic factors for TCC. These results suggest that PMN-MDSCs and M-MDSCs may be involved in tumor progression and could be prognostic factors and promising therapeutic targets in dogs with TCC.

Phenotypic Analysis of Circulating Myeloid Derived Suppressor Cells and Their Subpopulations in Egyptian Females with Breast Cancer: A Single-Centre Case-Control Study.

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with suppressive function that has been thoroughly documented in the setting of cancer. Our purpose was to evaluate levels of MDSC and their subsets in a cohort of Egyptian patients with breast cancer. Evaluation of peripheral blood total MDSC and its subset was done using multicolor flowcytometry in 30 malignant, 10 benign breast tumor patients and 10 healthy control females. BC patients had higher total MDSC levels compared to controls (p= 0.01) particularly the Monocytic MDSC (M-MDSC) and abnormal MDSC subsets (p = 0.001 and p <0.001, respectively). A tumor size > 2 cm exhibited significantly higher granulocytic MDSCs (G-MDSCs) compared to tumor size < 2 cm (p= 0.02) whereas abnormal MDSCs were significantly higher in patients with a tumor size < 2 cm (p = 0.037). MDSC and its subsets can be used as a prognostic marker of tumor size as well as a potential targets for treatment in breast cancer patients.

Study on the Impact of G-CSF Mobilization on the Level of MDSCs in Donor Peripheral Blood and Its Correlation with Patient Prognosis

Introduction:MDSCs are a newly discovered and heterogeneous population of immature bone marrow cells with immunosuppressive characteristics, capable of inhibiting innate and adaptive immune responses. Granulocyte colony-stimulating factor (G-CSF) is a member of the hematopoietic growth factor cytokine family responsible for the proliferation, maturation, differentiation, and survival of neutrophil lineage. In many hospitals in China, allo-HSCT procedures often involve administering G-CSF continuously for 5 days to healthy donors before collecting the graft, to mobilize white blood cells. This study discusses the impact of G-CSF mobilization on the absolute values and functions of total immunosuppressive myeloid-derived suppressor cells (MDSCs) and their subsets, M-MDSCs and P-MDSCs, in the peripheral blood of healthy donors. Furthermore, it explores the effects of transferring MDSCs from the graft to the patient's body on their prognosis and immune reconstitution. Method：From August 2022 to December 2022, a total of 72 donors and 72 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) were selected as the subjects at Lu Daopei Hospital in Beijing. Among the donors, there were 47 males and 25 females, with a median age of 34 years (19, 48). Among the patients, there were 33 males and 39 females, with a median age of 34 years (23, 45). The patients were diagnosed as acute leukemia or MDS in CR status and further categorized into infection group, graft-versus-host disease (GVHD) group, and no-event group based on post-transplantation outcomes. Peripheral blood samples were collected from the donors before and on the 5th day after mobilization, as well as from the graft and the patients. Flow cytometry was employed to determine the absolute counts of MDSCs and their subsets. Result 1. The absolute count of total MDSCs in the donor's peripheral blood before mobilization was 3/μl (2, 8), accounting for 0.1% (0.0, 0.2) of PBMCs, significantly lower than the absolute count of total MDSCs in the donor's peripheral blood after G-CSF mobilization, which was 2283/μl (1091, 5288), accounting for 6.4% (3.2, 9.5) of PBMCs, P&amp;lt;0.01. In the infection group, the absolute count and percentage of total MDSCs, P-MDSCs, and LOX1+P-MDSCs in the donor's peripheral blood after mobilization were higher than those in the donor's peripheral blood corresponding to the no-event group, and significantly higher than those in the donor's peripheral blood corresponding to the GVHD group. P&amp;lt;0.05. Similarly, the absolute count and percentage of total MDSCs, P-MDSCs, and LOX1+P-MDSCs in the correspondingdonor's peripheral blood inthe infection group after mobilization were higher than those in the donor's peripheral blood corresponding to the no-event group, and significantly higher than those in the donor's peripheral blood corresponding to the GVHD group., P&amp;lt;0.05. The absolute count and percentage of M-MDSCs in the infection group were higher than the no-event group and GVHD group, but the differences among the three did not reach statistical significance. Patients who developed infections after transplantation received a higher absolute count of total MDSCs from the graft compared to the no-event group, and significantly higher than the GVHD group, P&amp;lt;0.05. The mortality rate in the infection group was 30% (8/26), in the GVHD group was 14% (3/21), and in the no-event group was 0% (0/25). The ROC curve area under the curve (AUC) for the absolute count of total MDSCs per kilogram of body weight from the donor in the GVHD group was 0.669, with a cutoff of 1.7×107/kg, while in the infection group, the AUC was 0.661, with a cutoff of 4.3×107/kg. Conclusion: G-CSF can induce an increase in the content and enhancement of function of MDSCs in the donor's peripheral blood Maintaining a balance of MDSCs helps ensure immune homeostasis after transplantation.

EXTH-11. ADOPTIVE CELLULAR THERAPY OVERCOMES GLIOMA IMMUNE ESCAPE BY DISRUPTING MDSC PROLIFERATION AND RECRUITMENT

Abstract INTRODUCTION Our group has previously shown that adoptive cellular therapy (ACT) significantly extends survival in models of medulloblastoma, brain stem glioma, and glioblastoma. Further, ACT significantly decreases myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME), suggesting that ACT may ameliorate glioma-mediated immunosuppression. We hypothesize that ACT-mediated reduction of MDSCs is driven by cell proliferation and recruitment mechanisms, but these mechanisms have not been defined. In this study, we quantified the proportions and cell cycle states of MDSCs in the TME and peripheral lymphoid tissues as well as chemokines in serum to determine how ACT affects MDSC recruitment. METHODS ACT was performed in C57BL/6J mice bearing a syngeneic high-grade glioma derived from KR158B-luciferase cell line. The treatment platform included total body irradiation, hematopoietic stem cell rescue, total tumor ribonucleic acid (ttRNA) electroporated dendritic cells, and tumor-reactive T cells. Following ACT completion, we evaluated the proportions and cell cycle states of MDSCs using flow cytometry. Bromodeoxyuridine (BRDU) and 7-aminoactinomycin (7-AAD) defined cell cycle phases. Serum chemokines were measured using a membrane-based sandwich immunoassay. RESULTS We replicated our previous findings that ACT reduces the level of MDSCs in the TME. Additionally, ACT significantly decreased the proportion of MDSCs in S-phase in the TME. Conversely, levels of MDSCs in peripheral lymphoid tissue were significantly increased in mice treated with ACT, with a significant increase of MDSCs in S-phase. Analysis of serum chemokines revealed significant decreases in multiple chemokines implicated in MDSC recruitment such as CXCL13 and CXCL16. CONCLUSION These findings suggest that ACT decreases proliferation and chemotactic recruitment of MDSCs to the TME, which may also explain MDSC accumulation peripheral lymphoid tissue in ACT-treated mice. These immune mechanisms likely contribute to ACT’s efficacy against brain cancer, preventing tumor immune escape, and offer new therapeutic targets for optimizing cellular immunotherapies.

Clinicopathological and prognostic values of MET expression in pancreatic adenocarcinoma based on bioinformatics analysis.

Pancreatic adenocarcinoma (PAAD) is regarded as one of the most lethiferous cancers worldwide because treatment of pancreatic cancer remains challenging and mostly palliative. Little progress had been made to select certain reliable biomarkers as clinical prognosis. In this context, GSE28735 and GSE16515 were obtained from the Gene Expression Omnibus (GEO). GEO2R tool was used to recognize differentially expressed genes (DEGs). 351 DEGs were screened which included 230 up-regulated genes and 121 down-regulated genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the DEGs and associated signal pathways in the DAVID database. A protein-protein interaction (PPI) network was then constructed to screen 10 hub genes by STRING database and Cityscape software. Analyses of 10 hub genes were performed on GEPIA database and GSCA database, which revealed that MET was high expressed and significantly associated with survival of PAAD patients. Immunohistochemical staining showed that MET was higher expressed in PAAD tissues than adjacent tissues in 20 samples. The clinicopathological analysis revealed that high expression of MET was associated with the degree of differentiation, lymph node metastasis, vascular cancer thrombus and nerve invasion in PAAD tissues (P < .05). Furthermore, the Tumor Immune Estimation Resource (TIMER) database analyzed the correlation between the MET expression level and immune infiltration levels, which elucidated that MET expression was appreciably positively correlated with the infiltration levels of myeloid-derived suppressor cells (MDSCs). Here, these results strongly indicate MET is an unique prognostic biomarker. Its expression level is correlated with certain clinicopathological features and immune cell infiltration.

Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer.

New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.

A research on the influence of G-CSF mobilization on donor's peripheral blood MDSCs and its relationship with patient prognosis

ObjectiveTo discuss the effects of mobilization of healthy donors with granulocyte colony-stimulating factor (G-CSF) on the absolute values and functions of myeloid-derived suppressor cells (MDSCs) and subpopulations of M-MDSCs and P-MDSCs in their peripheral blood. In addition, this study also aims to investigate the impacts of the adoptively transferred MDSCs from the grafts to the patients on their prognosis and immune reconstitution. MethodsThe selection of 72 donors and 72 patients were conducted for allogeneic hematopoietic stem cell transplantation (allo-HSCT) from August 2022 to December 2022 at Lu Daopei Hospital in Beijing, China. Statistical calculations were performed by Wilcoxon signed-rank test, Kruskal Wallis test, χ2 test, Kaplan Meier test, and log-rank test to analyze the data. Results & ConclusionG-CSF induced significant amplification of MDSCs in the peripheral blood of donors in percentage and absolute values. Whether the level of P-MDSCs in patients conducted for the adoptive transfer of P - MDSCs is higher than 3.7× 107/kg or lower than 1.4× 107/kg leads to a poor prognosis of the patients. Ensuring a balanced state of MDSCs is crucial for effective immunotherapy. Transferring a high level of MDSCs from the graft to the patient's body is advantageous for the development of MDSCs while simultaneously inhibiting the proliferation of lymphocyte subgroups.

Baseline interleukin-6 is a prognostic factor for patients with metastatic breast cancer treated with eribulin

PurposeEribulin is a unique anti-cancer drug which can improve overall survival (OS) of patients with metastatic breast cancer (MBC), probably by modulating the tumor immune microenvironment. The aim of this study was to investigate the clinical significance of serum levels of immune-related and inflammatory cytokines in patients treated with eribulin. Furthermore, we investigated the association between cytokines and immune cells, such as myeloid-derived suppressor cells (MDSCs) and cytotoxic and regulatory T cells, to explore how these cytokines might affect the immune microenvironment.MethodsSixty-eight patients with MBC treated with eribulin were recruited for this retrospective study. The relationship of cytokines, including interleukin (IL)-6, to progression-free survival and OS was examined. CD4+ and CD8+ lymphocyte, MDSCs and regulatory T cell levels were determined in the blood by flow cytometry analysis.ResultsIn our cohort, patients with high IL-6 at baseline had shorter progression-free survival and OS compared with those with low IL-6 (p = 0.0017 and p = 0.0012, respectively). Univariable and multivariable analyses revealed that baseline IL-6 was an independent prognostic factor for OS (p = 0.0058). Importantly, CD8+ lymphocytes were significantly lower and MDSCs were significantly higher in patients with high IL-6, compared to those with low IL-6.ConclusionBaseline IL-6 is an important prognostic factor in patients with MBC treated with eribulin. Our results show that high IL-6 is associated with higher levels of MDSCs which suppress anti-tumor immunity, such as CD8+ cells. It appears that eribulin is not particularly effective in patients with high IL-6 due to a poor tumor immune microenvironment.

ARPC1B is a novel prognostic biomarker for kidney renal clear cell carcinoma and correlates with immune infiltration.

Background: Actin-related protein 2/3 complex subunit 1B (ARPC1B) is reported to be involved in tumorigenesis and progression. However, its role in kidney renal clear cell carcinoma (KIRC), correlation with tumor-infiltrating immune cells, and prognostic significance remain unclear. Methods: Data sets from the TCGA, GTEx, GEPIA, GEO, UALCAN, and CPTAC databases were extracted and analyzed to investigate the expression difference, prognosis, and clinicopathological features of ARPC1B. Single-sample Gene Set Enrichment Analysis (ssGSEA), CIBERSORT, and TISCH2 analysis were used to examine the relationship between ARPC1B expression and tumor immune infiltration in KIRC. The potential function of ARPC1B in KIRC was explored by GO functional annotation and KEGG pathway analysis. The TIDE algorithm was used to predict and analyze the relationship between ARPC1B expression and response to immune checkpoint blockade (ICB). The expression of ARPC1B was further validated by using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results: The study showed that ARPC1B expression was an independent prognostic factor of KIRC, with high ARPC1B expression being associated with poor overall survival (OS). Enrichment of GO annotation and pathway analysis showed multiple immune-related functional pathways affected by ARPC1B such as regulation of immune effector process, inflammatory response regulation, antigen processing and presentation, asthma, autoimmune thyroid disease, graft versus host disease, intestinal immune network for IgA production, and type I diabetic mellitus. Moreover, ARPC1B expression positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in KIRC. Importantly, high ARPC1B expression predicted a low response to ICB in KIRC. Conclusion: This study indicates that ARPC1B expression is an independent prognostic biomarker for OS in KIRC patients. High ARPC1B expression is closely associated with MDSCs and Tregs infiltration. These findings suggest that ARPC1B may serve as a biomarker for prognosis and immune infiltration in KIRC, potentially aiding in the development of novel treatment strategies to improve the survival outcomes for KIRC patients.

27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer

Zearalenone (ZEN) is a mycotoxin that extensively contaminates food and feed, posing a significant threat to public health. However, the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear. In this study, Sprague-Dawley (SD) rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w. for a duration of 14 days. The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine. Furthermore, ZEN exposure caused a significant reduction in the levels of apolipoprotein E (ApoE) and liver X receptor (LXR) (P < 0.05). Conversely, it upregulated the levels of myeloid-derived suppressor cells (MDSCs) markers (P < 0.05) and decreased the presence of 27-hydroxycholesterol (27-HC) in the intestine (P < 0.05). It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN. Additionally, a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal, breast, and lung cancers. These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine. Notably, ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.

Could the Crosstalk Between Myeloid-Derived-Suppressor Cells and Regulatory T Cells Have a Role in Beta-Thalassemia?

Secondary iron overload, alloimmunization, and increased risk of infection are common complications in patients with transfusion-dependent thalassemia (TDT). Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) play an essential role in preventing excessive immune response. This research aimed to study the interaction between Tregs and MDSCs in TDT patients and to evaluate the association of these cell types with disease severity. This case-control study included 26 patients with TDT and 23 healthy, age- and sex-matched controls. All patients were investigated for complete blood count (CBC), serum ferritin, and flow cytometric analysis of peripheral blood to detect Tregs, MDSCs, and MDSC subsets. A significant increase was observed in the frequencies of Tregs and MDSCs, particularly monocytic MDSCs (MO-MDSCs), in TDT patients compared with controls. The frequencies of these cells showed a direct association with ferritin level and total leukocyte count and an inverse association with hemoglobin level. Furthermore, a positive correlation was observed between Tregs and each of the total MDSCs and MO-MDSCs. Levels of Tregs and MDSCs increased in TDT and may probably have a role in suppressing the active immune systems of TDT patients.

Alpha-Fetoprotein as a Factor of Differentiation and Functional Activity of Myeloid-Derived Suppressor Cells.

We studied the role of alpha-fetoprotein (AFP) in regulation of differentiation and functional activity of human myeloid-derived suppressor cells (MDSC) in vitro. To obtain MDSC, CD11b+ cells were isolated from the peripheral blood of healthy donors followed by cytokine induction (IL-1β+GM-CSF) into the MDSC phenotype. The cell functions were assessed by the expression of indoleamine 2,3-dioxygenase (IDO) and arginase-1 (Arg1) and cytokine profile of the cell cultures. Native AFP did not affect the total number of MDSC and the percentage of polymorphonuclear MDSC (PMN-MDSC), but increased the number of monocytic MDSC (M-MDSC). AFP did not change the expression of Arg1, but in low concentrations (10 and 50 U/ml) increased the number of IDO-containing cells. AFP modulated the cytokine profile of CD11b+ cells: it reliably decreased the level of IL-19 (50 and100 U/ml) and showed a tendency to decrease the levels of IL-34, MMP-2, sCD163, CHI3L1, OPN and to increase the levels of IL-29, IL-32, APRIL, PTX3, and sTNF-R1. Thus, we have demonstrated a regulatory effect of native AFP at the level of MDSC generated from CD11b+ cells under conditions of cytokine induction in vitro.

Neutrophilic Myeloid-Derived Suppressor Cells and Severity in SARS-CoV-2 Infection.

While we strive to live with SARS-CoV-2, defining the immune response that leads to recovery rather than severe disease remains highly important. COVID-19 has been associated with inflammation and a profoundly suppressed immune response. To study myeloid-derived suppressor cells (MDSCs), which are potent immunosuppressive cells, in SARS-CoV-2 infection. Patients with severe and critical COVID-19 showed higher frequencies of neutrophilic (PMN)-MDSCs than patients with moderate illness and control individuals (P = .005). Severe disease in individuals older and younger than 60 years was associated with distinct PMN-MDSC frequencies, being predominantly higher in patients of 60 years of age and younger (P = .004). However, both age groups showed comparable inflammatory markers. In our analysis for the prediction of poor outcome during hospitalization, MDSCs were not associated with increased risk of death. Still, patients older than 60 years of age (odds ratio [OR] = 5.625; P = .02) with preexisting medical conditions (OR = 2.818; P = .003) showed more severe disease and worse outcome. Among the immunological parameters, increased C-reactive protein (OR = 1.015; P = .04) and lymphopenia (OR = 5.958; P = .04) strongly identified patients with poor prognosis. PMN-MDSCs are associated with disease severity in COVID-19; however, MDSC levels do not predict increased risk of death during hospitalization.