Levels Of Myeloid-derived Suppressor Cells Research Articles

VEGF-A as a prognostic indicator in advanced gastric and colorectal cancers and correlation with immune suppression involving myeloid-derived suppressor cells (MDSC).

250 Background: VEGF-A is important molecule should be controlled in cancer treatment since hypoxic and immunosuppressive conditions of tumor microenvironment are induced by VEGF-A. Myeloid-derived suppressor cells (MDSC), activated by chronic inflammation and VEGF-A, play critical roles in immunosuppression in patients with cancer. Methods: Serum levels of VEGF-A were measured by ELISA and circulating levels of MDSC were measured by Flow Cytometry (CD11b+, CD14-, CD33+). Patients with gastric and colorectal cancers were divided into two groups, high VEGF group (serum VEGF-A>330pg/ml) and lo group (≤330pg/ml). Results: Prognosis of stages III and IV gastric cancer with high VEGF-A was significantly worse than in low VEGF-A group, while difference was not significant in stages I and II. In colorectal cancer, the results were exactly same as found in gastric cancer. The levels of MDSC were significantly correlated with the levels of VEGF-A in patients with gastric and colorectal cancers. The levels of VEGF-A were also correlated with inflammatory markers including CRP and NLR (neutrophil to lymphocyte ratio), and inversely did to stimulation index of lymphocyte proliferation (SI: parameter of cellular immune reaction) and nutritional parameters such as albumin or rapid turnover protein. Conclusions: The observation in the present study suggest that VEGF-A is closely associated with inflammation-associated disease progression especially in advanced stages, and serve as useful marker of immunosuppression involving MDSC and prognosis in patients with gastric and colorectal cancers.

Tumor cells induce neural DKK1 expression to promote MDSC infiltration and subsequent T cell suppression.

Nerves are often overlooked as key components of the tumor microenvironment. However, the molecular mechanisms underlying the reciprocal interactions between tumors and nerves remain largely unknown. In this study, we analyzed data from The Cancer Genome Atlas (TCGA) and identified a significant association between DKK1 expression and poor prognosis, as well as a correlation between DKK1 expression and myeloid-derived suppressor cell (MDSC) infiltration in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC), two cancer types characterized by pronounced tumor-nerve interactions. Based on these findings, we hypothesize that tumors may induce DKK1 expression in nerves, and that nerve-derived DKK1 may promote MDSC infiltration and immunosuppression. To test this hypothesis, we employed a combination of experimental approaches, including in vitro co-culture of trigeminal ganglia with tumor cells, multiplex immunohistochemistry, and in vivo administration of DKK1 neutralizing antibodies. Our results indicate that tumor cells significantly induce DKK1 expression in ganglia in co-culture experiments. Additionally, in vivo orthotopic tumor models revealed that DKK1 levels were markedly elevated in both the plasma and ganglia of tumor-bearing mice. Neutralization DKK1 in vivo led to a reduction in MDSC levels and impaired MDSC-mediated T cell suppression in both HNSCC and PDAC orthotopic models. Furthermore, conditional deletion of neuronal DKK1 elucidated its role in MDSC infiltration and immune suppression. Our findings establish a novel molecular axis in which tumor cells modulate the immune microenvironment by inducing the expression of secreted proteins in nerves, thereby enriching the research landscape of the tumor microenvironment.

Cryptotanshinone alleviates immunosuppression in endometriosis by targeting MDSCs through JAK2/STAT3 pathway

BackgroundEndometriosis (EMS), a well-recognized chronic inflammatory disorder, characterized by significant immune dysregulation, in which myeloid-derived suppressor cells (MDSCs) are essential for facilitating immunosuppression and driving to disease progression. Cryptotanshinone (CTS) is an active compound capable of modulating MDSC-mediated immunosuppression; however, its therapeutic effects and mechanisms in the treatment of EMS remain unclear. PurposeThis study aims to investigate the therapeutic potential of CTS in modulating MDSCs through JAK2/STAT3 signaling pathway and to evaluate its effects on immune microenvironment and endometriotic lesion growth in EMS. MethodsTranscriptomic data (GSE141549) and single-cell RNA sequencing data (GSE213216) were analyzed to compare immune cell populations in control endometrium (CE), eutopic endometrium (EuE) and ectopic endometrium (EcE) of patients with EMS. Network pharmacology analysis, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) were utilized to explore the molecular mechanism of CTS's effects on MDSCs. A C57BL/6J EMS mice model was established to evaluate CTS's influence on MDSC-mediated immune response in vivo. Flow cytometry and immunofluorescence were used to analyze the immune cell populations, particularly MDSCs and CD8+ T cells. Ex vivo bone marrow (BM)-derived MDSCs were prepared to investigate the modulatory activities of CTS on the frequency and function of MDSCs. The impacts of CTS on JAK2/STAT3 pathway were further examined by western blot. ResultsBioinformatic analysis revealed that, among the three progression stages (CE, EuE, and EcE), the EcE stage exhibited a relatively elevated level of MDSCs and a reduced level of CD8+ T cells. Network pharmacological analysis, along with SPR and CETSA identified that CTS potentially modulates MDSCs in EMS by targeting the JAK2/STAT3 pathway. In vivo studies demonstrated that a relatively high dose of CTS treatment (60mg/kg) effectively inhibited lesion growth, reduced the population of MDSCs, and enhanced CD8+ T cell infiltration. Ex vivo experiments showed that CTS decreased the BM-derived MDSC frequency and rescued the suppressive ability of MDSC upon CD8+ T cells in a dose-dependent manner. Further mechanism analysis confirmed that CTS modulates the expression of immunosuppressive genes and proteins associated with MDSCs through JAK2/STAT3 pathway. ConclusionThis study is the first to demonstrate that CTS is a promising natural compound for EMS treatment by inhibiting MDSC accumulation and modulating MDSC-mediated immune responses. Its therapeutic efficacy is linked to the modulation of the JAK2/STAT3 signaling pathway.

IMMU-57. METHYL-B-CYCLODEXTRIN PARTIALLY REVERSES THE IMMUNOSUPPRESSIVE EFFECTS OF GLIOBLASTOMA DERIVED EXTRACELLULAR VESICLES ON LYMPHOCYTES

Abstract Extracellular vesicles (EVs) derived from glioblastoma (GBM) have been demonstrated in multiple studies to contribute to tumorigenesis, invasion, and immunosuppression. Our prior results demonstrate that EVs can induce the differentiation of myeloid-derived suppressor cells (MDSCs), which in turn impair T cell activation and proliferation in vitro. Methyl-B-Cyclodextrin (MBCD), a cholesterol depleting agent, can interfere with lipid rafts, which are cholesterol rich microdomains on the cellular membrane that act as a docking mechanism for EV uptake. Herein we demonstrate that MBCD can inhibit EV uptake and partially reverse the immunosuppressive effects of EVs on both monocytes and T cells. METHODS EVs were isolated using stepwise ultracentrifugation from GBM cultures. GBM derived EVs were then added to extracted monocytes from donor samples with or without MBCD for 72 hours under hypoxic conditions. The EV exposed monocytes were then co-cultured with T lymphocytes and cell proliferation was measured via flow cytometry. RESULTS Exposure to GBM-derived EVs induced MDSC differentiation in monocytes by at least 50% while the addition of MBCD reduced MDSC levels similar to that of the control group. Moreover, MBCD exposure resulted in increased T cell proliferation in the presence of EV treated monocytes compared to untreated samples. CONCLUSION MBCD can be used as a therapeutic agent to reverse MDSC induction by GBM derived EVs and can partially rescue T cell activation and proliferation.

Immunosuppressive MDSC and Treg signatures predict prognosis and therapeutic response in glioma

Glioma, a complex and aggressive brain tumor, is characterized by dysregulated immune responses within the tumor microenvironment (TME). We conducted a comprehensive analysis to elucidate the roles of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in glioma progression and their impact on the immune landscape. Using transcriptome data, we stratified glioma samples based on MDSC and Treg levels, revealing significant differences in patient survival probabilities. LASSO regression identified a gene panel associated with glioma prognosis, yielding a patient-specific risk score. Multivariate Cox regression confirmed the risk score’s correlation with overall survival. An ISS (immune suppressive score) system assessed the immune landscape’s impact on glioma progression and therapeutic response. Functional validation showed MDSC and Treg infiltration’s relevance in glioma progression and immune modulation. Hub genes in the black module, including CCL2, LINC01503, CXCL8, CLEC2B, TIMP1, and RGS2, were identified through MCODE analysis. RGS2 expression correlated with immune cell populations and varied in glioma cells. This study sheds light on MDSCs’ and Tregs’ roles in glioma pathogenesis, suggesting their potential as prognostic biomarkers and therapeutic targets for personalized immunotherapeutic strategies in glioma treatment.

The dynamic changes of circulating myeloid-derived suppressor cells (MDSCs) subsets in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy.

62 Background: Increased level of circulating myeloid-derived suppressor cells (MDSCs) have been associated with higher tumor stage, poorer survival, and poorer response to therapeutic agents in colorectal cancer (CRC). It has been reported that the common first-line chemotherapy involving combination with oxaliplatin mediated MDSCs depletion via induction of cell death. However, this phenomenon is yet to be further investigated since it only occurred in polymophonuclear MDSC (PMN-MDSC) subset, not in monocytic MDSC (M-MDSC). The present study aims to learn deeper on the dynamic changes of circulating MDSCs in response to oxaliplatin-based treatment in CRC patients. Methods: This was a prospective study that recruited 30 treatment-naïve patients with varying stage of CRC who were scheduled to receive oxaliplatin-based chemotherapy. Blood sampling was conducted prior and at several time points during and after chemotherapy. Multicolor flow cytometry assay was used to analyze the proportion of HLA-DR-, CD33+, and CD15+ (PMN-MDSC) and CD14+ (M-MDSC) cells within peripheral blood mononuclear cells (PBMCs). Other essential tumor biomarkers such as carcinoembryonic antigen (CEA) and tumor infiltrating lymphocytes (TILs) were assessed as well. As control, 14 healthy subjects were recruited. Results: Our result showed that circulating PMN-MDSCs was significantly higher in CRC patients compared to healthy subjects (p=0.003), whilst insignificant result was shown by M-MDSCs (p=0.890). Following chemotherapy, MDSCs level showed dynamic changes. Interestingly, a subgroup of CRC patients with decreased in both PMN- and M-MDSCs levels on D-14 chemotherapy were consistently showed a significant decreased of MDSCs level during and after therapy completion compared to baseline (p=0.0078). Conclusions: Circulating MDSCs level, particularly PMN-MDSCs in CRC patients was significantly higher compared to healthy subjects. Changes in both circulating PMN- and M-MDSCs levels at D-14 chemotherapy might have prognostic value in oxaliplatin-based chemotherapy.

Interleukin-1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma-induced increase in intra-hepatic immune cells.

Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC. Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1β levels in human and mouse serum were assessed. Interleukin-1β levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1β levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1-/-) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1β concentration. IL-1R1-/- mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver. Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.

Comprehensive mapping of immune perturbations associated with secondary hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome characterized by immune disorders. It is imperative to elucidate the immunophenotypic panorama and the interactions among these cells in patients. Human peripheral blood mononuclear cells were collected from healthy donors and sHLH patients and tested using multicolor flow cytometry. We used FlowSOM to explore and visualize the immunophenotypic characteristics of sHLH. By demonstrating the phenotypes of immune cells, we discovered that sHLH patients had significantly higher levels of CD56+ monocytes, higher levels of myeloid-derived suppressor cells, low-density neutrophil-to-T cell ratio, and higher heterogeneous T cell activation than healthy donors. However, natural killer cell cytotoxicity and function were impaired. We then assessed the correlations among 30 immune cell types and evaluated metabolic analysis. Our findings demonstrated polymorphonuclear myeloid-derived suppressor cells, CD56+ monocytes, and neutrophil-to-T cell ratio were elevated abnormally in sHLH patients, which may indicate an association with immune overactivation and inflammatory response. We are expected to confirm that they are involved in the occurrence of the disease through further in-depth research.

Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders.

Non-small cell lung cancer (NSCLC) represents a highly immunogenic malignancy. Immunologic tolerance facilitated by myeloid-derived suppressor cells (MDSCs) is implicated in primary or secondary resistance mechanisms in NSCLC. The potential role of APE1 in regulating NSCLC metastasis by targeting MDSCs remains uncertain. This study utilized a plasmid, Plxpsp-mGM-CSF, to induce elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in A549 cells. Tumor transplantation experiments involved A549, A549+GM-CSF, and A549+GM-CSF-siAPE1 cell lines. Evaluation encompassed MDSCs, Treg cells, IgG, CD3, and CD8 levels. Notably, lung cancer tissues and cells displayed markedly reduced APE1 expression. siAPE1 transfection significantly curtailed tumor growth compared to the A549+GM-CSF group. APE1 knockdown orchestrated immune system modulation in lung tumor mice, characterized by diminished MDSCs but augmented Treg cells, IgG, CD3, and CD8. Additionally, APE1 knockdown led to reduced levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12) and a concurrent upregulation of the anti-MDSC cytokine IL-1ra. Furthermore, APE1 knockdown impeded cell viability in both A549 and H1650 cells. Transplantation of A549-GM-CSF amplified MDSC levels, fostering accelerated tumor growth, while mitigating MDSC levels through APE1 knockdown hindered tumor progression and alleviated inflammatory infiltration in lung cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach for lung cancer prevention and treatment, presenting novel insights for NSCLC management.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Phase 1 study of anti–immunoglobulin-like transcript 3 (ILT3) monoclonal antibody (mAb) MK-0482 + pembrolizumab (pembro) in patients with recurrent inoperable glioblastoma (GBM).

2046 Background: For patients with GBM, treatment options are limited once the disease has recurred and become inoperable after standard first-line therapy. ILT3 is an inhibitory receptor expressed on monocytic myeloid cells, including tolerogenic dendritic cells and myeloid-derived suppressor cells (MDSCs). High expression of ILT3 on these immune cells has been associated with immune tolerance and suppression of T-cell function. Data have shown that GBMs have high ILT3 expression and high levels of MDSCs within the tumor microenvironment (TME). MK-0482 is a novel humanized IgG4 mAb targeting ILT3. Inhibition of ILT3 with MK-0482 may help relieve immunosuppression and improve T-cell function within the TME. In the expansion cohort of the first-in-human phase 1 study (MK-0482-001; NCT03918278), MK-0482 was evaluated in combination with pembro in a cohort of patients with recurrent inoperable GBM. The safety and efficacy data from this cohort are presented herein. Methods: Patients aged ≥18 y with their first recurrent inoperable GBM and a Karnofsky performance status (KPS) ≥80 were enrolled. Patients received MK-0482 750 mg Q3W + pembro 200 mg Q3W IV for up to a maximum of 35 cycles. The primary objective was to determine safety and tolerability of MK-0482 + pembro. Secondary objectives were to evaluate ORR, DCR (CR + PR + SD), and DOR by investigator assessment per Response Assessment in Neuro-Oncology (RANO). Exploratory objectives included evaluation of PFS per RANO and OS. Results: Overall, 25 patients were enrolled and received study treatment. At data cutoff (October 3, 2023), median follow-up duration was 9.3 mo (range, 5.6-14.5); treatment was ongoing in 1 patient. Median age was 56 y (range, 33-76). Most patients were male (72%), had a KPS of 80 (68%), and had IDH1 wild-type tumors (88%). All patients had previously received systemic therapy: 24 of 25 (96%) received prior temozolomide and 3 of 25 (12%) received prior glasdegib. Overall, 22 patients (88%) had an adverse event (AE); 10 patients (40%) had treatment-related AEs, most commonly (≥10%) arthralgia (12%), fatigue (12%), and increased ALT (12%). Grade 3 treatment-related AEs occurred in 2 patients (8%; increased ALT [n = 1] and fatigue [n = 1]). No grade 4 or 5 treatment-related AEs occurred. Four patients (16%) experienced immune-mediated AEs (hypothyroidism, n = 2; hepatitis, n = 1; pancreatitis, n = 1); all were grade 1 or 2. Confirmed ORR was 12% (3/25; 95% CI, 2.5-31.2), DCR was 32% (8/25; 14.9-53.5), and median DOR was 11.1 mo (range, 9.9-16.6+). Median PFS was 1.4 mo (95% CI, 1.3-2.9) and median OS was 9.3 mo (6.3-13.7); 6-/12-mo PFS and OS rates were 24%/16% and 72%/36%, respectively. Biomarker data will be included in the presentation. Conclusions: MK-0482 + pembro had a manageable AE profile with modest antitumor activity in patients with recurrent inoperable GBM. Clinical trial information: NCT03918278 .

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.

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.

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.

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.

MYELOID-DERIVED SUPPRESSOR CELLS TWO YEARS AFTER HEPATITIS C VIRUS ERADICATION USING DIRECTLY ACTING ANTIVIRALS.

Myeloid-derived suppressor cells (MDSCs) have immature morphology, relatively weak phagocytic activity, as well as some immunosuppressive functions. The capacity of MDSCs to inhibit T-cell-mediated immunological responses is their most notable functional characteristic. Down-regulating antitumor immune surveillance is one way that the expansion and activation of MDSCs contribute significantly to the occurrence and progression of tumors. Increased levels of MDSCs in patients with chronic hepatitis C virus (HCV) infection could suppress T-cell responses, promoting viral escape and hepatitis progression. This may make HCV-infected individuals more vulnerable to severe infections, hepatic and extra-hepatic tumors, and a diminished capacity to react to immunization. It is still unknown if effective HCV eradication with directly acting antivirals (DAAs) can restore immune functions and immune surveillance capacity. The purpose of this study was to observe the frequency of M-MDSCs (CD33+, CD11b+, and HLA-DR) in patients with a previous history of HCV, 2-3 years after virus eradication using DAA therapy. This study was conducted on 110 subjects: fifty-five subjects without liver cirrhosis who were treated with HCV using DAAs and attained SVR for a period of 2-3 years and 55 age- and gender-matched healthy controls. The study was conducted during the period from January to July 2022. Patients were recruited from the National Viral Hepatitis Treatment Unit, Alexandria University Hepatology outpatient clinic, and the Alexandria University Tropical Medicine outpatient clinic. The frequencies of MDSCs (CD33+CD11b + HLA-DR-) by flow cytometry were assessed. Even after the virus had been eradicated for longer than two years, MDSC levels in HCV-treated individuals were found to be considerably higher. In the HCV-treated group, the median number of MDSCs was 5, with an interquartile range (IQR) of 3.79-7.69. In contrast, the median for the control group was 3.1, with an IQR of 1.4-3.2 (P˂0.001). Successful DAA therapy leads to slow and partial immunological reconstitution, as demonstrated by the failure to attain normal levels of MDSC's 2 years after successful HCV eradication despite the normalization of laboratory parameters as well as the absence of liver fibrosis. The clinical implications of these findings should be thoroughly studied.

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.