Research Progress of Granulocytic Myeloid-derived Suppressor Cells in Non-small Cell Lung Cancer / 中国肺癌杂志

Granulocytic myeloid-derived suppressor cells (G-MDSCs) are one of the main subgroups of MDSCs, which are widely enriched in most cancers. It can inhibit the killing function of T-lymphocyte through the expression of arginase-1 (Arg-1) and reactive oxygen species (ROS), reshape the tumor immune microenvironment, and promote the occurrence and development of tumors. In recent years, more and more studies have found that G-MDSCs are significantly correlated with the prognosis and immunotherapy efficacy of patients with non-small cell lung cancer, and the use of drugs specifically targeting the recruitment, differentiation and function of G-MDSCs can effectively inhibit tumor progression. This article reviews the immunosuppressive effect of G-MDSCs in non-small cell lung cancer and the progress of related pathway targeting drugs.
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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.

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.

ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

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.

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.

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.

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.

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.

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

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.

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.

Predictive Role of Circulating Immune Cell Subtypes Early after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia

BACKGROUND AND OBJECTIVES: Cells of innate immunity normally recover in the first weeks to months after allogenenic hematopoietic stem cell transplantation (allo-HSCT). Their relevance in terms of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect is largely unknown. The predictive role of early recovery in the immune cells on acute GVHD and GVL effect after allo-HSCT was investigated in patients with acute leukemia who achieved the first complete remission. METHODS: Peripheral blood samples were taken at the median of 14 days (range, 12~29 days) after allo-HSCT. A cohort including 119 samples and characteristics of patients were analyzed. Immune cell populations were identified by flow cytometry. RESULTS: The median age was 49.0 years (range, 21~69) at transplantation. Univariate analysis showed that age less than 40 years old, lower frequencies of CD8+ T cells, invariant natural killer T (iNKT) cells, monocytic myeloid derived suppressor cells (M-MDSCs) and higher frequency of immature MDSCs were associated with occurrence of grade III–IV acute GVHD. Multivariate analyses showed that iNKT cells (hazard ratio (HR), 0.453, 95% CI, 0.091~0.844, p=0.024) and M-MDSCs (HR, 0.271, 95% CI, 0.078~0.937, p=0.039) were independent factors. Combination of higher frequencies of both cell subsets was associated with lower incidence of grade III–IV acute GVHD, whereas patients with lower frequency of iNKT cells and higher frequency of M-MDSCs showed significant higher probability of relapse. CONCLUSIONS: iNKT cells and M-MDSCs could be relevant cell biomarkers for predicting acute GVHD and/or relapse in acute leukemia patients treated with allo-HSCT.

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.

Cisplatin promotes heart failure in bladder cancer mice by impairing granulocytic myeloid-derived suppressor cells / 上海交通大学学报（医学版）

Objective: To investigate the effect of cisplatin on heart failure in bladder cancer mice by impairing granulocytic myeloid-derived suppressor cells (G-MDSCs). Methods: Fifty 8-week-old specific pathogen free (SPF) C3H/He healthy female mice were used to establish the bladder cancer model after subcutaneous injection of MBT-2 mice bladder cancer cells. The mice were divided into group A-E,10 mice in each group,and the group A was set as the blank control group. The group B-E mice were continuously intraperitoneally injected with 5 mg/ (kg•d) isoproterenol for 14 d to successfully establish the heart failure model. The group B was set as the control group. The mice were intraperitoneally injected with 7.5 mg/kg cisplatin every 48 h for chemotherapy,and killed at 14 d in the group C. G-MDSCs were identified,isolated and purified by flow cytometry. 1×107 purified G-MDSCs were intravenously injected into the group D mice via the tail vein every 7 d. The group E mice was treated by combining the procedure of the group C and the group D. The myocardial tissue of the mice was stained by hematoxylin-eosin staining. And the heart failure degree of the mice was analyzed by the heart weight/body weight ratio and the observation under the inverted phase contrast microscope. Results: Flow cytometry results showed that compared with the group B,the level of G-MDSCs in the circulation system of the group C mice was significantly decreased (P=0.000). Hematoxylin-eosin staining and Image J software analysis showed that compared with the group B,the heart weight/body weight ratio and the area of myocardial cells of the group C mice were significantly increased (P=0.001,P=0.002). However,after G-MDSCs injection,the above two indexes in the group D mice were decreased compared with those in the group B (P=0.000,P=0.011). After cisplatin/G-MDSCs combined treatment,the above two indexes in the group E were also decreased compared with those in the group C (P=0.000,P=0.001). Conclusion: G-MDSCs have cardioprotective effects,while cisplatin can facilitate heart failure by impairing G-MDSCs.

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.