Advances on myeloid-derived suppressor cells in hepatitis B virus infection / 中华临床感染病杂志

Myeloid-derived suppressor cells (MDSCs) are a group of immature and heterogeneous cells that can inhibit T cell function. In pathological conditions such as tumors, infections, and chronic inflammation, the large expansion of MDSCs is involved in processes of immune escape, immune tolerance and inflammatory reactions. MDSCs are also crucial in the pathophysiology of hepatitis B virus (HBV) infection, however, their activation, differentiation, and function during HBV infection are still unclear. This article reviews the general characteristics and roles of MDSCs in HBV infection, as well as related drug therapies, in order to provide information for further research on the related mechanism and potential targeted treatment.

Effect of Banxia Xiexintang-containing Intestinal Absorption Solution on PMN-MDSCs Apoptosis in Gastric Cancer Microenvironment / 中国实验方剂学杂志

ObjectiveTo observe the effect of Banxia Xiexintang （BXT）-containing intestinal absorption solution on the apoptosis of polymorphonuclear myeloid-derived suppressor cells （PMN-MDSCs） in gastric cancer microenvironment. MethodBXT-containing intestinal absorption solution was prepared， and gastric cancer cells and PMN-MDSCs were non-contact co-cultured in Transwell chamber to establish gastric cancer microenvironment. Cell counting kit-8 （CCK-8） assay was used to screen the optimal intervention concentration and time of 0-100% BXT-containing intestinal absorption solution prepared by 0.63 g·mL-1 reconstitution solution. Cells were classified into blank group， model group， oxaliplatin group （10 mg·L-1）， and BXT （26%， 18%， 10% BXT-containing intestinal absorption solution） group， and the apoptosis of PMN-MDSCs was detected by flow cytometry. The expression of apoptosis-related B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and cysteine-aspartic acid protease-3 （Caspase-3） in PMN-MDSCs was detected by Western blot. ResultAfter treatment for 24 h and 48 h， the PMN-MDSCs-inhibiting rate was increased by 5%， 50%， 75%， and 100% BXT-containing intestinal absorption solution compared with that in the blank group （P<0.05， P<0.01）. At 72 h， the PMN-MDSCs-inhibiting rate by 50% BXT-containing intestinal absorption solution was lower than that at 48 h （P<0.01）， and the PMN-MDSCs-inhibiting rate by 5%， 75%， and 100% BXT-containing intestinal absorption solution showed no significant difference from that at 48 h. Moreover， the half-maximal inhibitory concentration （IC50） at 48 h was 18.40%. Thus， 18% BXT-containing intestinal absorption solution and 48 h were the optimal intervention concentration and time. The survival rate of PMN-MDSCs in model group was higher than that in the blank group （P<0.05）， and the apoptosis rate was lower than that in the blank group （P<0.05）. Compared with model group， BXT containing intestinal absorption solution lowered the survival rate and raised apoptosis rate of PMN-MDSCs （P<0.05）， particularly the 26% BXT-containing intestinal absorption solution （P<0.05）. The expression of Bax and Caspase-3 in PMN-MDSCs was lower in the model group than in the blank group （P<0.05）， and the expression of Bcl-2 was higher in the model group than in the blank group （P<0.05）. The expression of Caspase-3 in PMN-MDSCs increased （P<0.05） and the expression of Bcl-2 decreased （P<0.05） in oxaliplatin group and BXT group compared with those in the model group. The expression of Bax rose in oxaliplatin group and BXT group （10% BXT-containing intestinal absorption solution） （P<0.05）. ConclusionBXT can induce the apoptosis of PMN-MDSCs by regulating the expression of apoptosis-related proteins Bax， Caspase-3， and Bcl-2 in gastric cancer microenvironment.

Effect of Banxia Xiexintang-containing Intestinal Absorption Solution on Migration and Invasion of PMN-MDSCs in Gastric Cancer Microenvironment / 中国实验方剂学杂志

ObjectiveTo observe the effect of Banxia Xiexintang containing intestinal absorption solution （BXCIAS） on migration and invasion of polymorphonuclear myeloid-derived suppressor cells （PMN-MDSCs） in gastric cancer microenvironment. MethodThe complex solution （containing 0.63 g·mL-1 crude drug） was prepared. Gastric cancer cells were subjected to non-contact co-culture with PMN-MDSCs in Transwell chamber to create gastric cancer microenvironment. Cell counting kit-8 （CCK-8） assay was used to screen the optimal intervention concentration and time of BXCIAS on PMN-MDSCs for subsequent experiment. The blank group， model group， FAK inhibitor group， and BXCIAS groups （26%， 18%， and 10%） were designed. Scratch assay and Transwell assay were employed to detect the migration and invasion ability of PMN-MDSCs， and enzyme-linked immunosorbent assay （ELISA） to measure the expression of vascular endothelial cell growth factor （VEGF） and matrix metalloproteinase-9 （MMP-9） in tumor microenvironment. The expression levels of PMN-MDSCs pathway-related proteins FAK， phosphorylated （p）-FAK， protein tyrosine kinase （Src）， and p-Src were detected by Western blot. ResultThe inhibition rates of PMN-MDSCs by 5%， 50%， 75%， and 100% BXCIAS at 48 h were higher than those at 24 h （P<0.05， P<0.01）. The inhibition rate of PMN-MDSCs by 50% BXCIAS at 72 h was lower than that at 48 h （P<0.01）， and the inhibition rates by 5% and 100% BXCIAS at 72 h were higher than those at 48 h （P<0.05， P<0.01）. There was no significant difference in the inhibition rate by other concentration levels at 48 h. The half-maximal inhibitory concentration （IC50） at 48 h was 18.09%， indicating that 18% BXCIAS and 48 h were the optimal concentration and time， respectively. The migration distance of PMN-MDSCs was large （P<0.01）， and the number of migrating and invading cells increased （P<0.01） in the mode group compared with those in the blank group. Compared with model group， FAK inhibitor and BXCIAS at different concentration decreased the migration distance of PMN-MDSCs （P<0.01）， and the number of migrating and invading cells （P<0.01）， especially the 26% BXCIAS （P<0.01）. The expression of PMN-MDSCs pathway-related proteins FAK， p-FAK， Src and p-Src （P<0.01） and the expression of VEGF and MMP-9 （P<0.01） were higher in the model group than in the blank group. Compared with model group， FAK inhibitor and BXCIAS （26%， 18%， 10%） decreased the expression of FAK， p-FAK， and Src （P<0.01）， and FAK inhibitor and 18% BXCIAS reduced the expression of p-Src （P<0.01）， and the expression of VEGF and MMP-9 （P<0.01）. ConclusionBXCIAS can inhibit the migration and invasion of PMN-MDSCs by down-regulating the expression of FAK， p-FAK， Src， and p-Src proteins in the FAK signaling pathway of PMN-MDSCs in gastric cancer microenvironment.

The antitumor activity of hPRDX5 against pancreatic cancer and the possible mechanisms

Recombinant human peroxiredoxin-5 (hPRDX5), isolated from anti-cancer bioactive peptide (ACBPs), shows a homology of 89% with goat peroxiredoxin-5 (gPRDX5) and is reported to display anti-tumor activity in vivo. Herein, we explored the effect of hPRDX5 and the responsible mechanism in treating pancreatic cancer. Tumor-bearing mice were randomly divided into normal PBS group and treatment group (n=5; 10 mg/kg hPRDX5). Flow cytometry was employed to examine lymphocytes, myeloid-derived suppressor cell subsets, and the function proteins of natural killer (NK) cells in peripheral blood, spleen, and tumor tissues of mice. Western blot was used to measure the protein expressions of the key nodes in TLR4-MAPK-NF-κB signaling pathway. The rate of tumor suppression was 57.6% at a 10 mg/kg dose in orthotopic transplanted tumor mice. Moreover, the population of CD3+CD4+T cells, NK cells, and CD3+CD8+T cells was significantly increased in the tumor tissue of the hPRDX5 group, while the proportion of granulocytic-myeloid-derived suppressor cells decreased slightly. In addition, after treatment with hPRDX5, the percentage of NK cells in blood increased more than 4-fold. Our findings indicated that hPRDX5 effectively suppressed pancreatic cancer possibly via the TLR4-MAPK-NF-κB signaling cascade; hence hPRDX5 could be a prospective immunotherapy candidate for treating pancreatic cancer.

Progress in mechanism of tumor-derived exosomes on myeloid-derived suppressor cells / 中华微生物学和免疫学杂志

Myeloid-derived suppressor cells (MDSCs) play an important immunosuppressive role in the tumor microenvironment. Tumor cells can regulate the immunosuppressive function of MDSCs in the tumor microenvironment through exosomes, thereby affecting the development of tumors. Tumor-derived exosomes (TEXs) promote the development of MDSCs and improve their immunosuppressive function in the tumor microenvironment mainly by participating in the processes such as intercellular information exchange and information transmission. Moreover, the miRNAs in TEXs will also be transferred to recipient cells to inhibit the immunosuppressive function of MDSCs by inducing the negative regulation of target genes. This review summarized the progress in the mechanism of TEXs on MDSCs.

Role of myeloid-derived suppressor cell in respiratory tract infections / 中华微生物学和免疫学杂志

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that are generated from the blockade differentiation of myeloid cells during pathological conditions. MDSC are regulatory immune cells with a potent immunosuppressive function, and play an important role in the development of various diseases including tumor, autoimmune diseases and trauma. Interestingly, emerging evidence shows that respiratory tract infections by viruses, bacteria and fungi can cause MDSC expansion and activation. MDSC levels are closely related to the symptoms of diseases caused by respiratory pathogens. Further investigation on the role and molecular mechanism of MDSC expansion and activation in respiratory tract infections will contribute to the development of novel strategies for the prevention and treatment of diseases caused by respiratory pathogens. Here, we summarized the role of MDSC in respiratory viral, bacterial and fungal infections and the relevant molecular mechanisms, aiming to provide a reference for further investigating the role of MDSC in respiratory tract infections.

Roles of Myeloid-derived Suppressor Cells in Breast Cancer Metastasis / 中国医学科学院学报

Breast cancer patients with bone,liver and lung metastases tend to have a poor prognosis.According to Paget's "seed and soil" theory,metastatic cancer cell "seeds" must fall on congenial target organ "soil".Studies have shown that myeloid-derived suppressor cells(MDSCs)can be recruited at the site of breast cancer metastasis in advance and play a role in the metastasis of breast cancer cells.This paper reviews the biological characteristics of MDSCs,the roles of MDSCs in peripheral circulation,prometastatic niche,and metastatic site during breast cancer metastasis,as well as the research progress of MDSCs-targeted treatment of breast cancer metastasis.

Influence of hepatocellular carcinoma microenvironment on myeloid-derived suppressor cells / 临床肝胆病杂志

Myeloid-derived suppressor cells (MDSCs) are a group of immature bone marrow cells with an immunosuppressive effect, and they are abundant in tumor patients and can induce tumor cells to escape the killing of immune cells and thus promote the development, progression, and metastasis of tumor. In recent years, its role in hepatocellular carcinoma microenvironment has attracted more and more attention, but the mechanisms of its recruitment and differentiation in hepatocellular carcinoma microenvironment have not been clearly elucidated. This article mainly summarizes the mechanism of action of tumor cells and tumor stromal cells in hepatocellular carcinoma microenvironment (such as hepatic stellate cells, tumor-associated fibroblasts, and tumor-associated endothelial cells) in the recruitment and differentiation of MDSCs, and it is proposed to target MDSCs as an adjuvant therapy to enhance the potential value of immunotherapy for liver cancer.

Effects of Signaling Activation of Bone Morphogenetic Protein 2 on the Differentiation and Infiltration of Regulatory T Lymphocytes in Tumors / 中国医学科学院学报

Objective To determine whether the signaling activation of bone morphogenetic protein 2(BMP2)can induce myeloid-derived suppressor cells(MDSC)to secret transforming growth factor β(TGF-β),further enhancing the differentiation and infiltration of regulatory T lymphocytes(Treg)into tumor tissue. Methods The BMP2-induced mRNA and protein expression of TGF-β in MDSC was detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA),respectively.The effect of BMP2-induced TGF-β secretion by MDSC on Treg differentiation was then determined by flow cytometry.Finally,we implanted the recombined human bone morphogenetic protein 2(rhBMP2)collagen gels into tumor-burdened mice to examine the role of BMP2 in Treg differentiation via MDSC-secreted TGF-β

Correlation of peripheral myeloid-derived suppressor cells with hepatitis c virus infection / 中国输血杂志

【Objective】 To investigate the correlation of peripheral myeloid-derived suppressor cells (MDSC) with hepatitis c virus (HCV) infection. 【Methods】 109 voluntary blood donors who donated blood during February 2018 to September 2020 at Guangzhou Blood Center were recruited in this study. They were assigned to chronic hepatitis c (CHC) group (n=48), spontaneous clearance (SC) group (n=29) and healthy donors (control) group (n=32) according to the results of anti-HCV and HCV RNA tests. Blood samples were drawn from the participants and peripheral blood mononuclear cells (PBMC) were freshly isolated, followed by staining with fluorescently-labeled antibody against cell surface markers of MDSC, which were then applied to the detection of monocytic- (M) and polymorphonuclear (PMN)-MDSC by flow cytometry. Parameters for liver function including alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), total bilirubin (TBIL) and direct bilirubin (DBIL) were also measured. One-way ANOVA tests were applied to compare the differences of M- and PMN-MDSC and liver function between three study groups. For pairwise comparisons, P values were adjusted for multiple comparisons by Bonferroni correction (Pc). 【Results】 The frequencies of M-MDSC (%) in CHC, SC and HC were 1.39±0.86, 0.85±0.63 and 0.57±0.23, respectively (P0.05). In addition, AST (34.4±19.2 vs 23.0±7.78 U/L) and GGT (40.8±31.4 vs 22.3±7.40 U/L) level were higher in CHC compared with control (Pc<0.05 and Pc<0.01, respectively). 【Conclusion】 The level of peripheral M-MDSC was significantly elevated in chronic HCV infected donors, which would related to the progression of chronicity after HCV infection.

The role and mechanism of myeloid-derived suppressor cells in mice with nonalcoholic steatohepatitis / 中国医师杂志

Objective To investigate the effects of myeloid-derived suppressor cells (MDSCs) on nonalcoholic steatohepatitis mice.Methods (1) Male C57BL/6 mice aged 6-8 weeks were randomly divided into normal diet group,CDAA group(choline deficient amino acid diet) and CSAA group (choline sufficient amino acid diet).(2) After the success of the non-alcoholic steatohepatitis model,serum was collected from some mice to detect biochemical indexes;Liver tissue was retained for microscopic observation by hematoxylin-eosin (HE) staining;The changes of T cell subsets in peripheral blood of mice in each group were detected by flow cytometry.In addition,The proportion and subtype of CD1 lb + Gr-1 + MDSCs cells in liver,spleen,blood and bone marrow were also detected by flow cytometry.(3)The bone marrow-derived Gr-1highLy-6G+ was purified by magnetic bead sorting technique,and the purified Gr-1highLy-6G+ was transferred into non-alcoholic steatohepatitis (NASH) mice by tail vein injection.The role of MDSCs in NASH was analyzed by detection of serological indexes of liver function and pathological dyeing.Results (1) There was no significant difference in body weight and liver index between the groups (P ＞ 0.05).Serological indicators:alanine aminotransferase (ALT),aspartate aminotransferase (AST),blood glucose,interleukin (IL)-6 and interferon-γ (INF-γ) in the model group were significantly higher than those in the normal group (P ＜ 0.01);microscopic findings:the liver in CDAA,CSAA group showed varying degrees of steatosis;the steatosis in CDAA group was much more severe.(2) Flow cytometry showed that ① the percentage of CD4 + CD8-T and CD4-CD8 + T decreased and CD4/CD8 ratio decreased in CDAA group;② the bone marrow MDSCs of CDAA group is lower than that of normal group (P ＜ 0.05);the MDSCs of peripheral blood in CDAA group is lower than that of normal group (P ＞ 0.05);the MDSCs of liver in CDAA group is lower than that of normal group (P ＜ 0.01).③ subgroup comparison,bone marrow,liver CD11 b + Gr-1 high Ly-6G + (G-MDSC):CDAA group ＞ normal group (P ＜ 0.0l),CD11 b + Gr-1 dim Ly-6G-(M-MDSC) showed a downward trend,CDAA group ＜ normal group;(3) Serum AST and ALT levels of NASH mice who receiving Gr-1highLy-6G+ MDSCs from normal bone marrow were significantly decreased (P ＜ 0.001),and histopathological changes were alleviated.Conclusions (1) The NASA mouse model can be successfully established on the CDAA diet.(2) The CDAA-induced NASH mice may have immune dysfunction,mainly manifesting in the change of bone marrow MDSCs subpopulations and the increase of CDllb + Gr-1highLy-6G+ (G-MDSC).(3) MDSCs derived from normal mouse bone marrow can alleviate the pathological changes of NASH.

Function of myeloid-derived suppressor cells and strategy of reversal immunosuppression / 中国肿瘤生物治疗杂志

@#Myeloid-derived suppressor cells (MDSCs) are a group of highly heterogeneous immunosuppressive cells produced in the bone marrow, which accumulate in large amounts under pathological conditions such as malignant tumors. MDSCs are the significant cell subsets that reduce patients' response to traditional treatment and promote tumor progression. In recent years, immune checkpoint blockade and adoptive transfusion of engineered T cells have significantly prolonged the survival of many patients with advanced malignant tumors, but the effective rate from 15% to 40% in some solid tumors including lung cancer, colorectal cancer etc., which is closely related to the immunosuppressive microenvironment in solid cancers. With the accumulation in tumor microenvironment, MDSCs reduce the anti-tumor immune response of patients by inhibiting T cell or NK cell proliferation and function, which is the key mechanism for patients tolerating to immunotherapy. Therefore, clarifying the accumulation and functional characteristics of MDSCs is an important research direction to explore the improvement of restoring immunotherapy. This article will systematically elaborate the regulatory mechanism of MDSC production, aggregation and immunosuppressive function, and outline the latest research progress of targeted MDSC therapy

Advances in research on infection of Myeloid-derived suppressor cells / 医学研究生学报

Myeloid-derived suppressor cells (MDSCs) are newly discovered cells derived from bone marrow that suppress immunity, playing an immunosuppressive role in tumors, infections, and autoimmune diseases. It has been confirmed in disease model studies that their immunosuppressive effect is mainly achieved by suppressing the function of T cells. At present, the treatment of infectious diseases is still a major obstacle, especially in the treatment of chronic infectious diseases. Studies have found that MDSCs have increased aggregation in infectious diseases. As MDSCs are gaining more attention in infectious diseases, their potential therapeutic effects may be further explored. This article mainly reviews the immunosuppressive mechanisms of MDSCs in infections such as bacteria, viruses, parasites and fungi and their relationship with the diseases.

Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs)

Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor-bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate NF-κB signaling. Moreover, expression of PD-L1 and CD80 on PD-1+ MDSCs was higher than on PD-1− MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in PD-1+ MDSCs than in PD-1− MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that PD-1+ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules.

IL-12 Enhances Immune Response by Modulation of Myeloid Derived Suppressor Cells in Tumor Microenvironment / 전남의대학술지

Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature cells that play a critical role in tumor associated immune suppression. In tumor conditions, the population of MDSCs increases. The main feature of these cells is their ability to suppress the T cell response in antigen specific or nonspecific manners depending on the condition of T cell activation. IL-12 can modulate MDSC in preliminary reports, so we investigated how IL-12 can affect MDSC in a tumor microenvironment. After implanting tumor based cells on syngeneic host, 4T-1/BALB/c or EL4/C57BL6 mice, MDSCs (Gr1+CD11b+) were isolated from splenocytes. Isolated MDSCs were treated with GM-CSF with or without IL-12 and analyzed based on their phenotypes and functions. Treatment of MDSC with IL-12 increased co-stimulatory molecules of CD80, CD86, OX-40L, enhancing the DC phenotype (CD11c) and maturation markers such as p-NF-κB and p-GSK3β. In addition to a change of surface markers, T-cell suppressive function of MDSC after IL-12 treatment was significantly improved compared with the control MDSC. In addition, PD-L1+F4/80+ macrophages, which show aninhibitory effect in phagocytosis, were decreased after IL-12 treatment. The changes of cell surface expression of CD80, CD86, MHC class II were also shown in vivo. Our results showed that the IL-12 can modulate MDSC into APC and recover the macrophage function. These results suggested that IL-12 plays a role in improving the tumor immune microenvironment through MDSC modulation.

Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes / Imunosenescência: participação de linfócitos T e células mieloides supressoras nas alterações da resposta imune relacionadas ao envelhecimento

ABSTRACT Healthy aging is partly related to appropriate function of the immune system. As already reported, some changes in this system are observed, including reduced number and repertoire of T cells due to thymic involution, accumulation of memory T cells by chronic infections, homeostatic proliferation compensating for the number of naïve T cells, decreased proliferation of T cells against a stimulus, telomere shortening, replicative senescence of the T cells, and inflammaging, besides the accumulation of myeloid-derived suppressor cells. The purpose of this article is to clarify each of these changes, aiming to minimize limitations of immunosenescence. If such associations can be established, these cells may be used as early and less invasive markers of aging-related diseases, as well as to indicate interventions, evaluate the efficacy of interventions and be a tool to achieve longevity with quality of life.

RESUMO O envelhecimento saudável está relacionado, pelo menos em parte, com a função adequada do sistema imunológico. Isso porque já foi relatado que, com o envelhecimento, algumas mudanças desse sistema são observadas, como a diminuição da percentagem e do repertório de células T pela involução tímica, acúmulo de células T de memória por infecções crônicas, compensação do número de células T naïve por proliferação homeostática, diminuição da capacidade de proliferação das células T frente a um estímulo, encurtamento dos telômeros, senescência replicativa das células T, e inflammaging, além do acúmulo de células mieloides supressoras. Este artigo visa esclarecer cada uma das mudanças, mencionadas, com o intuito de buscar meios de minimizar as limitações da imunosenescência. Caso seja possível estabelecer tais relações, essas células podem ser utilizadas como marcadores precoces e pouco invasivos de doenças relacionadas ao envelhecimento, além da possibilidade de serem utilizadas para indicar intervenções, avaliar a eficácia das intervenções e como ferramenta para alcance da longevidade com qualidade de vida.

Influence of gelatin sponge microparticles-TACE on myeloid-derived suppressor cells in peripheral blood of patients with Barcelona clinic liver cancer classification stage B hepatocellular carcinoma / 中国介入影像与治疗学

Objective: To investigate the influence of gelatin sponge microparticles-TACE (GSMs-TACE) on myeloid-derived suppressor cells (MDSCs) in peripheral blood of patients with Barcelona clinic liver cancer (BCLC) classification stage B hepatocellular carcinoma (HCC). Methods: Five patients with clinically diagnosed BCLC B-stage HCC (HCC group) underwent GSMs-TACE. Flow cytometry was used to detect the frequency of MDSCs (the proportion of MDSCs clusters to HLA-DR-cell) in the peripheral blood of patients before GSMs-TACE and 10 days as well as 30 days after operation, respectively. Seven healthy volunteers (normal control group) were enrolled. The MDSCs frequency of normal control group was detected simultaneously with HCC group before GSMs-TACE. Statistical analysis was performed to compare the differences of the frequency of MDSCs in HCC patients before and after GSMs-TACE. And the frequency of MDSCs of HCC group was compared with that of normal control group. Results: The frequency of MDSCs in peripheral blood of patients with HCC before GSMs-TACE was (30.26±12.12)%, which decreased to (10.22±3.79)% after 10 days and decreased to (7.33±3.38)% after 30 days (P<0.001). Pairwise comparison showed that the frequency of MDSCs at 30 days (P<0.001) and 10 days (P=0.011) after GSMs-TACE was lower than that before operation,respectively. The frequency of preoperative MDSCs of HCC group was statistically higher than that of normal control group ([30.26±12.12]% vs [3.41±1.89]%, t=5.876, P<0.001). Conclusion: The frequency of MDSCs in peripheral blood of patients with BCLC B-stage HCC significantly reduced after GSMs-TACE treatment. GSMs-TACE treatment has positive regulation effect on the immune function of patients.

Cancer-associated fibroblasts mediate differentiation of myeloid-derived suppressor cells in pancreatic cancer through IL-6/STAT3 pathway / 第二军医大学学报

Objective To explore the mechanism and biological significance of differentiation of myeloid-derived suppressor cells (MDSCs) mediated by cancer-associated fibroblasts (CAFs) in the pancreatic ductal adenocarcinoma (PDAC), so as to provide theoretical and experimental basis for revealing the roles of CAFs and MDSCs in promoting the progression of pancreatic cancer by remodeling the pancreatic cancer microenvironment. Methods We isolated and purified primary CAFs from PDAC tumor tissues, and screened the up-regulated cytokines in CAFs by quantitative real-time PCR and enzyme-like immunosorbent assay. The human foreskin fibroblasts (HFFs) were used as controls. Human peripheral blood mononuclear cells (PBMCs) were cultured with supernatant of CAFs and HFFs, respectively. The differentiation of PBMCs was observed and the mechanisms of the above cytokines in regulating the differentiation and recruitment of MDSCs were studied. Results The biomarkers (α-smooth muscle actin [α-SMA] and fibroblast activation protein a [FAPa]) were detected in the isolated primary CAFs, but not found in the HFFs. The expression levels of interleukin 6 (IL-6), stromal cell-derived factor 1 (SDF-1) and monocyte chemotactic protein 1 (MCP-1) in the culture supernatant were significantly gradually increased in the CAFs than those in the HFFs (all P0.01). Compared with culture supernatant of HFFs, the culture supernatant of CAFs promoted more PBMCs to differentiate into CD13-high expression neutrophil-like MDSCs (CD13hi-nMDSCs; P0.01). IL-6 human recombinant protein alone in the co-culture system could induce the differentiation of PBMCs into CD13hi-nMDSCs (P0.01). SDF-1 or MCP-1 human recombinant protein alone could not induce the increase of CD13hi-nMDSCs subpopulation. IL-6 neutralizing antibody or signal transducer and activator of transcription 3 (STAT3) blocker FLLL32 could significantly inhibit the differentiation induced by the culture supernatant of CAFs (P0.05). Conclusion CAFs can promote the differentiation of PBMCs into CD13hi-nMDSCs via the IL-6/STAT3 pathway.

Research Progress of Different Subtypes of Myeloid-derived Suppressor Cells and Traditional Chinese Medicine Regulation Effect in Tumor Microenvironment / 中国实验方剂学杂志

The diagnosis and treatment methods for cancer are being improved continually, but the mortality of cancer still remains high. At present, the academic circle has realized deficiency of existing treatment ideas, and the concept of cancer cells has been gradually changed from "extremely extinct" to "peaceful coexistence". The concept of "survival with tumors" is universally accepted in the cancer academia. The tumor microenvironment is the place where tumor cells survive and develop. Therefore, regulation of the tumor microenvironment has become an important new strategy for tumor treatment. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells that have immunosuppressive properties on T cells in the tumor microenvironment and play an important role in tumor immune escape. Now, therapy with MDSCs in the tumor microenvironment as the treatment targets also provides new ideas for the tumor treatment. As MDSCs subpopulations are similar with neutrophils and monocytes, they can be divided into two major subtypes:granulocyte-like myeloid-derived suppressor cells (G-MDSCs) and monocyte-myeloid-derived suppressor cells(M-MDSCs). But how to differ these two subtypes from neutrophils and monocytes. What are the differences in the functional characteristics of different subtypes of MDSCs. How do they accumulate, differentiate, and exert immunosuppressive effects through different pathways. Traditional Chinese medicine(TCM) has always been good at modulating the body's microenvironment. More and more researches have shown that, the recruitment, amplification and activation of MDSCs can be effectively inhibited by TCM compound and its active ingredients, providing scientific basis for Chinese medicine targeting MDSCs in the tumor microenvironment. However, which specific pathways could regulate G-MDSCs or M-MDSCs is still in need of further studies. Most previous literature focus on the overall level of MDSCs, while the this paper would be based on the specific subpopulations of MDSCs to clarify the biological characteristics of these two subtypes of MDSCs, so as to achieve more precise targeted therapy in the tumor microenvironment.

Effect of Yiqi Jianpi Huayu Recipe Combined with 5-FU on Growth and Immune Function of Subcutaneous Transplanted Tumor in MFC Bearing Mice / 中国实验方剂学杂志

Objective:To discuss the effect of Yiqi Jianpi Huayu recipe (YQJPHY) combined with 5-fluorouracil(5-FU) on the growth and immune function of subcutaneous transplanted tumor in MFC tumor bearing 615 mice. Method:Twenty-four mice were inoculated subcutaneously to establish the transplanted tumor model of gastric cancer in mice, and then randomly divided into model control group, YQJPHY (20 g·kg-1)group, 5-FU (25 mg·kg-1) group and (YQJPHY+5-FU) combined group, with 6 rats in each group. After the last administration, the transplanted tumor, spleen and thymus were stripped completely. The tumor inhibition rate, thymus and spleen index were calculated. Flow cytometry was used to determine the content of myeloid-derived suppressor cells (MDSCs) and its subtype polykaryotype cells (PMN-MDSC), single karyotype cells (M-MDSC) in both peripheral blood and tumor tissue, and macrophages and their M1 type, M2 type, T lymphocyte, B lymphocyte, and natural killer cells (NK cells) in peripheral blood. Expressions of arginase-1(Arg-1) and inducible nitric oxide synthesis (iNOS) gene in tumor tissues were detected by Real-time PCR. Result:Compared with model control group, the weight of mice in YQJPHY group increased, whereas the weight of tumor, the weight of tumor, the index of thymus and spleen decreased in 5-FU group(PPPPPPPP+,CD4+,CD8+ T cell group decreased(PPPPPPConclusion:YQJPHY can better inhibit the growth of subcutaneous transplanted tumor when combined with 5-FU, and improve immune status after chemotherapy. The mechanism may be related to the decrease of MDSCs content and the increase of T cell and macrophages content.