Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and im...Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.展开更多
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancrea...BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancreatic cancer. The present study was to investigate a specific subset of MDSCs in patients with pancreatic cancer and the mechanism of MDSCs increase in these patients. METHODS: Myeloid cells from whole blood were collected from 37 patients with pancreatic cancer, 17 with cholangiocarcinoma, and 47 healthy controls. Four pancreatic cancer cell lines were co- cultured with normal peripheral blood mononudear cells (PBMCs) to test the effect of tumor cells on the conversion of PBMCs to MDSCs. Levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and arginase activity in the plasma of cancer patients were analyzed by enzyme-linked immunosorbent assay. RESULTS: CD14+/CD11b+/HLA-DR MDSCs were increased in patients with pancreatic or bile duct cancer compared with those in healthy controls, and this increase was correlated with clinical cancer stage. Pancreatic cancer cell lines induced PBMCs to MDSCs in a dose-dependent manner. GM-CSF and arginase activity levels were significantly increased in the se rum of patients with pancreatic cancer. CONCLUSIONS: MDSCs were tumor related: tumor cells induced PBMCs to MDSCs in a dose-dependent manner and circulating CD14+/CD11b+/HLA-DR- MDSCs in pancreatic cancer patients were positively correlated with tumor burden. MDSCs might be useful markers for pancreatic cancer detection and progression.展开更多
Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in traum...Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD1 lb+/Gr-l+ cells, proliferation and apoptosis of CD4+ T cells were determined. Ar- ginase activity and arginase-1 (Arg-1) protein expression of splenic CDllb+/Gr-I+ cells, and de- layed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD1 lb+/Gr-l+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD1 lb+/Gr-l+ ceils. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.展开更多
Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC ...Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. Myeloid-derived suppressor cells(MDSCs)have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM–TACE to evaluate the effect on the immune function of HCC patients.Methods: Eight patients diagnosed with HCC underwent GSM–TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China;we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry(FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after surgery.Results: MDSC frequency after GSM–TACE had a significant downward trend. Pre-TACE, it was 30.73% ? 11.93%,decreasing to 18.60% ? 11.37% at 10 days after operation. This decrease was not statistically significant(P > 0.05). MDSC frequency was even lower 30 days after TACE(7.63% ? 7.32%) than at 10 days after TACE(P < 0.05), and there was a significant difference compared with pre-TACE(P < 0.001). We evaluated tumor response at 30 days after GSM–TACE according to the Modified Response Evaluation Criteria in Solid Tumors(mRECIST), and all eight patients showed partial response(PR).Conclusion: Our results confirmed that GSM–TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.展开更多
The effects of granulocyte colony-stimulation-factor (G-CSF) on stem cell mobilization and its impact on the amplification of myeloid-derived suppressor cells (MDSCs) of donor mice were ex- amined. A mouse model o...The effects of granulocyte colony-stimulation-factor (G-CSF) on stem cell mobilization and its impact on the amplification of myeloid-derived suppressor cells (MDSCs) of donor mice were ex- amined. A mouse model of stem cell mobilization was established by consecutive subcutaneous injec- tion of 100 μg/kg G-CSF for 5 days. The blood from the donor mice was routinely examined during mobilization. Stem cells and MDSCs were analyzed by flow cytometry. The immunosuppressive mole- cules derived from MDSCs in serum and spleen, including hydrogen dioxide (H202) and nitric oxide (NO), and the activity of nitric oxide synthase (NOS) were determined during the mobilization. Apop- tosis of T lymphocytes was assessed by using Annexin-V/PI. During stem cell mobilization, the number of lymphocytes and white blood cells in the peripheral blood was increased, and peaked on the 4th day. The number of stem cells in G-CSF-treated mice was significantly greater than that in controls (P〈0.01). The expansions of MSDCs were also observed after G-CSF mobilization, with a more notable rate of growth in the peripheral blood than in the spleen. The activity of NOS and the production of NO were increased in the donor mice, and the serum H202 levels were approximately 4-fold greater than the con- trois. Consequently, apoptosis of T lymphocytes was increased and showed a positive correlation with the elevated percentage of MDSCs. It was concluded that G-CSF could provide sufficient peripheral blood stem cells for transplantation. Exogenous administration of G-CSF caused the accumulation of MDSCs in the peripheral blood and the spleen, which could lead to apoptosis ofT lymphocytes and may offer a new strategy for the prevention and treatment of graft versus host disease.展开更多
Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established t...Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases.Methods In this study,murine B16LS melanoma cells were transplanted into the posterior compartment(PC)of the eye of C57BL/6 mice.Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation,examined by flow cytometry for their expression of Gr1,CD11b,F4/80,RAE-1,and Mult-1,and further isolated for MDSCs and natural killer(NK)cells.The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma(IFN-γ)by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay.The impact of IFN-γon liver metastases was examined via selectively depleting IFN-γin vivo.Results The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+as well as CD11b+Gr1+F4/80−MDSCs.MDSCs significantly enhanced the generation of IFN-γtogether with the cytotoxicity of the NK cells.Furthermore,these effects were cell-cell contact-dependent.Although IFN-γwas not of a toxic nature to the melanoma cells,it profoundly inhibited B16LS cell proliferation.Depleting IFN-γin vivo led to increased liver metastases.Conclusion All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response.Thus,the MDSCs’performance in different tumor models would need more investigation to boost current immunotherapy modalities.展开更多
Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).M...Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.展开更多
Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tumor itself and conventional anti-tumor treatments such as c...Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tumor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppressor cells(MDSCs) are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8+ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be critical for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes(VSSP) is a nanoparticulated adjuvant specifically designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8+ T cells, Th1 polarization, and enhances CD8+ T cell response in tumorfree mice. Currently, four cancer vaccines using VSSP as the adjuvant are in PhaseⅠand Ⅱ clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specific CD8+ T cell responses in two immunocompromised scenarios; in tumor-bearing mice and during chemotherapy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vaccine adjuvants currently in preclinical or clinical studies.展开更多
Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed ...Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.展开更多
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 rol...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(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.展开更多
The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells(Hp SCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantati...The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells(Hp SCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by Hp SCs, including the marked expansion of myeloid-derived suppressor cells(MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. Hp SC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how Hp SCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.展开更多
Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indi...Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.展开更多
Growing evidence suggests that myeloid-derived suppressor cells (MDSCs),which have been named "immature myeloid cells" or "myeloid suppressor cells" (MSCs),play a critical role during the progression of cancer...Growing evidence suggests that myeloid-derived suppressor cells (MDSCs),which have been named "immature myeloid cells" or "myeloid suppressor cells" (MSCs),play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases (MMPs),chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells (CSCs) are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may "hijack" MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.展开更多
Background Hemorrhagic shock is usually associated with complicated immune and inflammatory responses, which are sometimes crucial for the prognosis. As regulators of the immune and inflammatory system; proliferation,...Background Hemorrhagic shock is usually associated with complicated immune and inflammatory responses, which are sometimes crucial for the prognosis. As regulators of the immune and inflammatory system; proliferation, migration, distribution and activation of myeloid-derived suppressor cells (MDSCs) are intimately linked to the inflammation cascade. Methods In a model of severe hemorrhagic shock, thirty-five rats were randomly divided into control, sham, normal saline resuscitation (NS), hypertonic saline resuscitation (HTS), and hydroxyethyl starch resuscitation (HES), with seven in each group. MDSCs were analyzed by flow cytometric staining of CD11b/c*Gra~ in peripheral blood mononuclear cells (PBMC), spleen cell suspensions, and bone marrow nucleated cells (BMNC). Simultaneously, the expressions of arginase-1 (ARG-1) and inducible nitric oxide synthase (iNOS) mRNA in MDSCs were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results In the early stage after hemorrhagic shock, fluid resuscitation and emergency treatment, the MDSCs in the PBMC of NS, HTS and HES groups markedly increased, and MDSCs in BMNC of these groups decreased accordingly, significantly different to the control group. In hemorrhagic shock rats infused with HTS at the early resuscitation stage, MDSCs in PBMC increased about 2 and 4 folds, and MDSCs in BMNC decreased about 1.3 and 1.6 folds, as compared to the sham group respectively, with statistically significant difference. Furthermore, compared to the NS and HES groups, the MDSCs in PBMC of HTS group increased 1.6 and 1.8 folds with statistically significant differences; the MDSCs decrease in BMNC was not significant. However, there was no statistically significant difference in MDSCs of spleen among the five groups. In addition, compared to the control, sham, NS and HES groups, the ARG-1 and iNOS mRNA of MDSCs in PBMC, spleen and BMNC in the HTS group had the highest level of expression, but no statistically significant differences were noted. Conclusions In this model of rat with severe and controlled hemorrhagic shock, small volume resuscitation with HTS contributes to dramatically early migration and redistribution of MDSCs from bone marrow to peripheral circulation, compared to resuscitation with NS or HES.展开更多
Myelodysplastic syndrome (MDS) is a group of clonal .hematopoietic stem cell disorders, characterizedby varying degrees ot peripheral cytopema caused by ineffective dysplasia of the myeloid lineages. MDS also has a ...Myelodysplastic syndrome (MDS) is a group of clonal .hematopoietic stem cell disorders, characterizedby varying degrees ot peripheral cytopema caused by ineffective dysplasia of the myeloid lineages. MDS also has a high risk of progression to acute myeloid leukemia. But the role of immune abnormalities in the pathogenesis of MDS is still not clear. Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature cells derived from the bone marrow. In the recent years, MDSCs were reported to play an important role in suppressing lymphocytes in tumor-bearing animal models and cancer patients. This could be one of the mechanisms on tumor immune evasion, which aggravates the development and growth of tumors. In a mice model, MDSCs are characterized by co- expression of GR1 and CDllb. In humans, the phenotype of MDSCs was accepted as Lin- HLA-DR- CD33+.l In the present study, we investigated the level of circulating MDSCs (Lin- HLA-DR- CD33+) in patients with MDS and evaluated the association between MDSCs and malignancy in MDS. METHODS Patients Thirty-five patients with MDS (24 men and 11 women, median age 59 years (age range 21-83), including refractory anemia (n=3); refractory anemia with ringed sideroblasts (n=3); refractory cytopenia with multilineage dysplasia (n=9); refractory anemia with excess blast-I (n=4); refractory anemia with excess blast-II (n=16)), and without other systemic diseases, were enrolled in the present study. All the patients underwent diagnosis in the Department of Hematology, General Hospital of Tianjin Medical University from March 2011 to April 2012, according to the diagnostic criteria of MDS proposed between 2007 and 2008. After treatment for three months, 14 MDS patients were investigated again for their MDSCs changes. Twenty normal healthy individuals were selected as controls (9 men and 11 women, median age 34 years (age range 26-82)). The study was approved by the Ethics Committee of Tianjin Medical University. Informed written consent was obtained from all the patients and normalindividuals in accordance with the Declaration of Helsinki Flow cytometric analysis Peripheral blood samples were collected in EDTA- anticoagulant tubes from the patients and normal individuals. The number of circulating MDSCs was measured by using flow cytometry (FCM) assay. The markers used in the assay were anti-CD33-APC, anti-LIN- FITC (CD3, CD14, CD16, CD19, CD20, CD56) and anti- HLA-DR-PE antibodies (BD Biosciences, USA). The number of stem cells from the bone marrow, which was collected in heparin-anticoagulant tubes, was measured by FCM using anti-CD34-PerCP antibodies (BD Biosciences). Data acquisition and analysis were carried out by using FACS-Calibur flow cytometer (BD Biosciences), with the Cell Quest software (Becton Dickinson, version 3.1).展开更多
Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in bot...Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in both diagnostics and treatment,the incidence and mortality rate of GI cancer are on the rise.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions,such as infection and inflammation,and this expansion is of particular relevance to cancer.MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors,favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence.Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patientswith cancer,and potentially as a novel treatment target.In the present review,the mechanisms underlying the immunosuppressive functions of MDSCs are described,and recent researches concerning the involvement of MDSCs in the progression,prognosis,and therapies of GI cancer are reviewed.The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.展开更多
Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dos...Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin(DOX)to enhance immune efficacy in NB.Methods:Bagg albino(BALB/c)mice were used as tumor-bearing mouse models by injecting Neuro-2a cells,and MDSCs were eliminated by DOX or dopamine(DA)administration.Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX,5.0 mg/kg DOX,50.0 mg/kg DA,and control groups(n=20).The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition.NB antigen-specific cytotoxic T cells(CTLs)were prepared.Tumor-bearing mice were randomly divided into DOX,CTL,anti-ganglioside(GD2),DOX+CTL,DOX+anti-GD2,and control groups.Following low-dose DOX administration,immunotherapy was applied.The levels of human leukocyte antigen(HLA)-I,CD8,interleukin(IL)-2 and interferon(IFN)-γin peripheral blood,CTLs,T-helper 1(Th1)/Th2 cytokines,perforin,granzyme and tumor growth were compared among the groups.The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.Results:The slowest tumor growth(F=6.095,P=0.018)and strongest MDSC inhibition(F=14.632,P=0.001)were observed in 2.5 mg/kg DOX group.Proliferation of T cells was increased(F=448.721,P<0.001)and then decreased(F=2.047,P=0.186).After low-dose DOX administration,HLA-I(F=222.489),CD8(F=271.686),Th1/Th2 cytokines,CD4^(+)and CD8^(+)lymphocytes,granzyme(F=2376.475)and perforin(F=488.531)in tumor,IL-2(F=62.951)and IFN-γ(F=240.709)in peripheral blood of each immunotherapy group were all higher compared with the control group(all ofP values<0.05).The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.Conclusions:Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression,thereby fostering immune efficacy in NB.展开更多
The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role ...The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role in maintaining feto-maternal tolerance,little is known about the role of MDSCs in pregnancies with intrauterine growth retardation(IUGR).Here,we reported that the activation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)during pregnancy was closely associated with fetal growth.In humans,class E scavenger receptor 1(SR-E1),a distinct marker for human PMN-MDSCs,was used to investigate PMN-MDSC function during pregnancy.Continuous activation of SR-E1+PMN-MDSCs was observed in all stages of pregnancy,accompanied by high cellular levels of ROS and arginase-1 activity,mediated through STAT6 signaling.However,SR-E1+PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity,lower arginase-1 activity and ROS levels,and decreased STAT6 phosphorylation level,which were accompanied by an increase in inflammatory factors,compared with those in normal pregnancies.Moreover,the population of SR-E1+PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR.In mice,decreases in cell population,suppressive activity,target expression levels,and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies,which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice.Interestingly,the growth-promoting factors(GPFs)secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development.These findings collectively support that PMN-MDSCs have another new role in pregnancy,which can improve adverse neonatal outcomes.展开更多
Numerous recent studies have shown that myeloid-derived suppressor cells(MDSCs),a strongly heterogeneous population of immunosuppressive cells,are dysregulated in the presence of many cancers.MDSCs present different p...Numerous recent studies have shown that myeloid-derived suppressor cells(MDSCs),a strongly heterogeneous population of immunosuppressive cells,are dysregulated in the presence of many cancers.MDSCs present different phenotypes and play prominent roles in the tumor microenvironment.To date,gene therapies targeting MDSCs are the most innovative and flexible methods to specifically modify the tumor microenvironment.Here,we summarize current studies related to the phenotypes,functions,and mechanisms of MDSCs and explore the therapeutic landscape of chemokines that affect the balance between subpopulations of MDSCs.展开更多
Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF)...Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF).Methods A total of 25 HBV-ACLF patients展开更多
基金Supported by National Natural Science Foundation of China,No.82320108022,No.82322076 and No.82104466.
文摘Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.
基金supported by grants from the National Natural Science Foundation of China(81071775,81272659,81101621,81160311,81172064,81001068,81272425 and 81101870)National“Eleventh Five-Year”Scientific and Technological Support Projects(2006BAI02A13-402)+1 种基金Key Projects of Science Foundation of Hubei Province(2011CDA030)Research Fund of Young Scholars for the Doctoral Program of Higher Education of China(20110142120014)
文摘BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancreatic cancer. The present study was to investigate a specific subset of MDSCs in patients with pancreatic cancer and the mechanism of MDSCs increase in these patients. METHODS: Myeloid cells from whole blood were collected from 37 patients with pancreatic cancer, 17 with cholangiocarcinoma, and 47 healthy controls. Four pancreatic cancer cell lines were co- cultured with normal peripheral blood mononudear cells (PBMCs) to test the effect of tumor cells on the conversion of PBMCs to MDSCs. Levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and arginase activity in the plasma of cancer patients were analyzed by enzyme-linked immunosorbent assay. RESULTS: CD14+/CD11b+/HLA-DR MDSCs were increased in patients with pancreatic or bile duct cancer compared with those in healthy controls, and this increase was correlated with clinical cancer stage. Pancreatic cancer cell lines induced PBMCs to MDSCs in a dose-dependent manner. GM-CSF and arginase activity levels were significantly increased in the se rum of patients with pancreatic cancer. CONCLUSIONS: MDSCs were tumor related: tumor cells induced PBMCs to MDSCs in a dose-dependent manner and circulating CD14+/CD11b+/HLA-DR- MDSCs in pancreatic cancer patients were positively correlated with tumor burden. MDSCs might be useful markers for pancreatic cancer detection and progression.
基金supported by grants from the Foundation of Science and Technology of Wuhan City(No.201161038339)Health Department of Hubei Province of China(No.QJX2010-4)+1 种基金Natural Science Foundation of Hubei Province of China(No.2011CDB205)National"Twelfth Five-Year"Plan for Science&Technology Support(No.2012BAI11B00)
文摘Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD1 lb+/Gr-l+ cells, proliferation and apoptosis of CD4+ T cells were determined. Ar- ginase activity and arginase-1 (Arg-1) protein expression of splenic CDllb+/Gr-I+ cells, and de- layed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD1 lb+/Gr-l+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD1 lb+/Gr-l+ ceils. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.
基金Supported by a grant from National Natural Science Foundation of China(grant number 81571783)National Major Project for Infectious Diseases of China(2017ZX100203205005)
文摘Purpose: A series of clinical studies have established the safety and efficacy of transcatheter arterial chemoembolization(TACE) with gelatin sponge microparticles(GSMs) in treating hepatocellular carcinoma(HCC). HCC can lead to obvious necrosis inside tumors, especially larger ones, although it is unclear whether such necrotic tumor tissue can induce favorable immune reactions against the tumor. Myeloid-derived suppressor cells(MDSCs)have immunosuppressive functions and are currently considered a very important cell type affecting tumor immunity. This study observed changes in MDSC frequency in peripheral blood before and after GSM–TACE to evaluate the effect on the immune function of HCC patients.Methods: Eight patients diagnosed with HCC underwent GSM–TACE treatment in the Hepatobiliary Interventional Department of Beijing Tsinghua Chang Gung Hospital, Beijing, China;we followed up with the patients over a period of 30 days post-surgery. We used flow cytometry(FCM) to quantify the frequency of MDSCs in peripheral blood before TACE, 10 days after surgery and 30 days after surgery.Results: MDSC frequency after GSM–TACE had a significant downward trend. Pre-TACE, it was 30.73% ? 11.93%,decreasing to 18.60% ? 11.37% at 10 days after operation. This decrease was not statistically significant(P > 0.05). MDSC frequency was even lower 30 days after TACE(7.63% ? 7.32%) than at 10 days after TACE(P < 0.05), and there was a significant difference compared with pre-TACE(P < 0.001). We evaluated tumor response at 30 days after GSM–TACE according to the Modified Response Evaluation Criteria in Solid Tumors(mRECIST), and all eight patients showed partial response(PR).Conclusion: Our results confirmed that GSM–TACE was beneficial for improving anti-tumor immunity in the treatment of HCC.
基金supported by grants from Department of Health of Hubei Province(No.JX5B07)Department of Health of Wuhan(No.WX09B02)
文摘The effects of granulocyte colony-stimulation-factor (G-CSF) on stem cell mobilization and its impact on the amplification of myeloid-derived suppressor cells (MDSCs) of donor mice were ex- amined. A mouse model of stem cell mobilization was established by consecutive subcutaneous injec- tion of 100 μg/kg G-CSF for 5 days. The blood from the donor mice was routinely examined during mobilization. Stem cells and MDSCs were analyzed by flow cytometry. The immunosuppressive mole- cules derived from MDSCs in serum and spleen, including hydrogen dioxide (H202) and nitric oxide (NO), and the activity of nitric oxide synthase (NOS) were determined during the mobilization. Apop- tosis of T lymphocytes was assessed by using Annexin-V/PI. During stem cell mobilization, the number of lymphocytes and white blood cells in the peripheral blood was increased, and peaked on the 4th day. The number of stem cells in G-CSF-treated mice was significantly greater than that in controls (P〈0.01). The expansions of MSDCs were also observed after G-CSF mobilization, with a more notable rate of growth in the peripheral blood than in the spleen. The activity of NOS and the production of NO were increased in the donor mice, and the serum H202 levels were approximately 4-fold greater than the con- trois. Consequently, apoptosis of T lymphocytes was increased and showed a positive correlation with the elevated percentage of MDSCs. It was concluded that G-CSF could provide sufficient peripheral blood stem cells for transplantation. Exogenous administration of G-CSF caused the accumulation of MDSCs in the peripheral blood and the spleen, which could lead to apoptosis ofT lymphocytes and may offer a new strategy for the prevention and treatment of graft versus host disease.
基金supported by the Fundamental Research Funds for the Central Universities(No.2021yjsCXCY086).
文摘Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases.Methods In this study,murine B16LS melanoma cells were transplanted into the posterior compartment(PC)of the eye of C57BL/6 mice.Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation,examined by flow cytometry for their expression of Gr1,CD11b,F4/80,RAE-1,and Mult-1,and further isolated for MDSCs and natural killer(NK)cells.The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma(IFN-γ)by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay.The impact of IFN-γon liver metastases was examined via selectively depleting IFN-γin vivo.Results The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+as well as CD11b+Gr1+F4/80−MDSCs.MDSCs significantly enhanced the generation of IFN-γtogether with the cytotoxicity of the NK cells.Furthermore,these effects were cell-cell contact-dependent.Although IFN-γwas not of a toxic nature to the melanoma cells,it profoundly inhibited B16LS cell proliferation.Depleting IFN-γin vivo led to increased liver metastases.Conclusion All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response.Thus,the MDSCs’performance in different tumor models would need more investigation to boost current immunotherapy modalities.
文摘Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.
文摘Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tumor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppressor cells(MDSCs) are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8+ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be critical for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes(VSSP) is a nanoparticulated adjuvant specifically designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8+ T cells, Th1 polarization, and enhances CD8+ T cell response in tumorfree mice. Currently, four cancer vaccines using VSSP as the adjuvant are in PhaseⅠand Ⅱ clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specific CD8+ T cell responses in two immunocompromised scenarios; in tumor-bearing mice and during chemotherapy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vaccine adjuvants currently in preclinical or clinical studies.
基金supported by the Postdoctoral Research Funds of Hebei Medical University(30705010016-3759)Natural Science Foundation of China(32272328)+4 种基金Natural Science Foundation of Hebei Province(B2022321001)National Key Research Project of Hebei Province(20375502D)Postdoctoral Research Project of Hebei Province(B2022003031)Science and Technology Research Program of Hebei Provincial Colleges(QN2023229)Hebei Provincial Key Laboratory of Nutrition and Health(2023YDYY-KF05)。
文摘Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.
基金supported by National Key R&D Program of China(No.2019YFE0111800)National Natural Science Foundation of China(Nos.T2192972,81872923,and 81903904)the CAMS Innovation Fund(2022-I2M-1-014,China).
文摘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(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.
基金Supported by National Science Council,No.NSC 101-2314-B-182A-040-MY2 and No.CMRPG6A0523
文摘The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells(Hp SCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by Hp SCs, including the marked expansion of myeloid-derived suppressor cells(MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. Hp SC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how Hp SCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.
基金supported by the Key Project of National Natural Science Foundation of China(82130062,82241062 and 81930057)the National Key Research and Development Program of China(2022YFA1104604)+1 种基金the Key Project of Military Medical Innovation Program of Chinese PLA(18CXZ026 and BLJ18J006)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-076)。
文摘Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.
基金supported by the National Basic Research Program of China (973 Program) (No 2010CB529403)the National Natural Science Foundation of China (Nos 30725035 and 30930103)
文摘Growing evidence suggests that myeloid-derived suppressor cells (MDSCs),which have been named "immature myeloid cells" or "myeloid suppressor cells" (MSCs),play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases (MMPs),chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells (CSCs) are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may "hijack" MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.
基金Science Foundation of China (No. 81272075), Zhejiang Provincial Natural Science Foundation of China (No. Y2100430), and the Zhejiang Provincial Education and Research Foundation of China (No. Y201019154).
文摘Background Hemorrhagic shock is usually associated with complicated immune and inflammatory responses, which are sometimes crucial for the prognosis. As regulators of the immune and inflammatory system; proliferation, migration, distribution and activation of myeloid-derived suppressor cells (MDSCs) are intimately linked to the inflammation cascade. Methods In a model of severe hemorrhagic shock, thirty-five rats were randomly divided into control, sham, normal saline resuscitation (NS), hypertonic saline resuscitation (HTS), and hydroxyethyl starch resuscitation (HES), with seven in each group. MDSCs were analyzed by flow cytometric staining of CD11b/c*Gra~ in peripheral blood mononuclear cells (PBMC), spleen cell suspensions, and bone marrow nucleated cells (BMNC). Simultaneously, the expressions of arginase-1 (ARG-1) and inducible nitric oxide synthase (iNOS) mRNA in MDSCs were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results In the early stage after hemorrhagic shock, fluid resuscitation and emergency treatment, the MDSCs in the PBMC of NS, HTS and HES groups markedly increased, and MDSCs in BMNC of these groups decreased accordingly, significantly different to the control group. In hemorrhagic shock rats infused with HTS at the early resuscitation stage, MDSCs in PBMC increased about 2 and 4 folds, and MDSCs in BMNC decreased about 1.3 and 1.6 folds, as compared to the sham group respectively, with statistically significant difference. Furthermore, compared to the NS and HES groups, the MDSCs in PBMC of HTS group increased 1.6 and 1.8 folds with statistically significant differences; the MDSCs decrease in BMNC was not significant. However, there was no statistically significant difference in MDSCs of spleen among the five groups. In addition, compared to the control, sham, NS and HES groups, the ARG-1 and iNOS mRNA of MDSCs in PBMC, spleen and BMNC in the HTS group had the highest level of expression, but no statistically significant differences were noted. Conclusions In this model of rat with severe and controlled hemorrhagic shock, small volume resuscitation with HTS contributes to dramatically early migration and redistribution of MDSCs from bone marrow to peripheral circulation, compared to resuscitation with NS or HES.
基金This study was partly supported by the National Natural Science Foundation of China (No. 81170472), the Application Bases and Advanced Technology Research Program of Tianjin (No. 09JCYBJC11200), the Special Fund for Health-Scientific Research in the Public Interest (No. 201202017), the Medical Scientific Research Foundation of Tianjin (No. 2012KZ103), and the Special Anticancer Fund of Scientific Planning Project of Tianjin (No. 12ZCDZSY 17900).
文摘Myelodysplastic syndrome (MDS) is a group of clonal .hematopoietic stem cell disorders, characterizedby varying degrees ot peripheral cytopema caused by ineffective dysplasia of the myeloid lineages. MDS also has a high risk of progression to acute myeloid leukemia. But the role of immune abnormalities in the pathogenesis of MDS is still not clear. Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature cells derived from the bone marrow. In the recent years, MDSCs were reported to play an important role in suppressing lymphocytes in tumor-bearing animal models and cancer patients. This could be one of the mechanisms on tumor immune evasion, which aggravates the development and growth of tumors. In a mice model, MDSCs are characterized by co- expression of GR1 and CDllb. In humans, the phenotype of MDSCs was accepted as Lin- HLA-DR- CD33+.l In the present study, we investigated the level of circulating MDSCs (Lin- HLA-DR- CD33+) in patients with MDS and evaluated the association between MDSCs and malignancy in MDS. METHODS Patients Thirty-five patients with MDS (24 men and 11 women, median age 59 years (age range 21-83), including refractory anemia (n=3); refractory anemia with ringed sideroblasts (n=3); refractory cytopenia with multilineage dysplasia (n=9); refractory anemia with excess blast-I (n=4); refractory anemia with excess blast-II (n=16)), and without other systemic diseases, were enrolled in the present study. All the patients underwent diagnosis in the Department of Hematology, General Hospital of Tianjin Medical University from March 2011 to April 2012, according to the diagnostic criteria of MDS proposed between 2007 and 2008. After treatment for three months, 14 MDS patients were investigated again for their MDSCs changes. Twenty normal healthy individuals were selected as controls (9 men and 11 women, median age 34 years (age range 26-82)). The study was approved by the Ethics Committee of Tianjin Medical University. Informed written consent was obtained from all the patients and normalindividuals in accordance with the Declaration of Helsinki Flow cytometric analysis Peripheral blood samples were collected in EDTA- anticoagulant tubes from the patients and normal individuals. The number of circulating MDSCs was measured by using flow cytometry (FCM) assay. The markers used in the assay were anti-CD33-APC, anti-LIN- FITC (CD3, CD14, CD16, CD19, CD20, CD56) and anti- HLA-DR-PE antibodies (BD Biosciences, USA). The number of stem cells from the bone marrow, which was collected in heparin-anticoagulant tubes, was measured by FCM using anti-CD34-PerCP antibodies (BD Biosciences). Data acquisition and analysis were carried out by using FACS-Calibur flow cytometer (BD Biosciences), with the Cell Quest software (Becton Dickinson, version 3.1).
基金National Natural Science Foundation of China,Grant/Award Numbers:81772957,82002546China Postdoctoral Science Foundation,Grant/Award Number:2020M672815+3 种基金National Key R&D Program of China,Grant/Award Number:2017YFA0503900Science and Technology Program of Guangdong Province in China,Grant/Award Number:2019B030301009Industry and Information Technology Foundation of Shenzhen,Grant/Award Number:20180309100135860SZU Top Ranking Project,Grant/Award Number:86000000210。
文摘Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in both diagnostics and treatment,the incidence and mortality rate of GI cancer are on the rise.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions,such as infection and inflammation,and this expansion is of particular relevance to cancer.MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors,favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence.Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patientswith cancer,and potentially as a novel treatment target.In the present review,the mechanisms underlying the immunosuppressive functions of MDSCs are described,and recent researches concerning the involvement of MDSCs in the progression,prognosis,and therapies of GI cancer are reviewed.The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.
基金National Natural Science Foundation of China(No.81472503)。
文摘Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin(DOX)to enhance immune efficacy in NB.Methods:Bagg albino(BALB/c)mice were used as tumor-bearing mouse models by injecting Neuro-2a cells,and MDSCs were eliminated by DOX or dopamine(DA)administration.Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX,5.0 mg/kg DOX,50.0 mg/kg DA,and control groups(n=20).The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition.NB antigen-specific cytotoxic T cells(CTLs)were prepared.Tumor-bearing mice were randomly divided into DOX,CTL,anti-ganglioside(GD2),DOX+CTL,DOX+anti-GD2,and control groups.Following low-dose DOX administration,immunotherapy was applied.The levels of human leukocyte antigen(HLA)-I,CD8,interleukin(IL)-2 and interferon(IFN)-γin peripheral blood,CTLs,T-helper 1(Th1)/Th2 cytokines,perforin,granzyme and tumor growth were compared among the groups.The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.Results:The slowest tumor growth(F=6.095,P=0.018)and strongest MDSC inhibition(F=14.632,P=0.001)were observed in 2.5 mg/kg DOX group.Proliferation of T cells was increased(F=448.721,P<0.001)and then decreased(F=2.047,P=0.186).After low-dose DOX administration,HLA-I(F=222.489),CD8(F=271.686),Th1/Th2 cytokines,CD4^(+)and CD8^(+)lymphocytes,granzyme(F=2376.475)and perforin(F=488.531)in tumor,IL-2(F=62.951)and IFN-γ(F=240.709)in peripheral blood of each immunotherapy group were all higher compared with the control group(all ofP values<0.05).The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.Conclusions:Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression,thereby fostering immune efficacy in NB.
基金supported by grants from the following institutions:the High-level Talent Start-up Funding of Southern Medical Universitythe National Natural Science Foundation of China(grant numbers:31700061,81971420 and 81991511)+2 种基金the Guangdong Special Support Program for Youth Science and Technology Innovation Talents(grant number:2019TQ05Y585)the National Natural Science Foundation of Guangdong(grant number:2019A1515011435)the Science and Technology Program of Guangzhou(grant number:201904010073).
文摘The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role in maintaining feto-maternal tolerance,little is known about the role of MDSCs in pregnancies with intrauterine growth retardation(IUGR).Here,we reported that the activation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)during pregnancy was closely associated with fetal growth.In humans,class E scavenger receptor 1(SR-E1),a distinct marker for human PMN-MDSCs,was used to investigate PMN-MDSC function during pregnancy.Continuous activation of SR-E1+PMN-MDSCs was observed in all stages of pregnancy,accompanied by high cellular levels of ROS and arginase-1 activity,mediated through STAT6 signaling.However,SR-E1+PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity,lower arginase-1 activity and ROS levels,and decreased STAT6 phosphorylation level,which were accompanied by an increase in inflammatory factors,compared with those in normal pregnancies.Moreover,the population of SR-E1+PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR.In mice,decreases in cell population,suppressive activity,target expression levels,and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies,which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice.Interestingly,the growth-promoting factors(GPFs)secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development.These findings collectively support that PMN-MDSCs have another new role in pregnancy,which can improve adverse neonatal outcomes.
基金supported by grants from the National Natural Science Foundation of China(No.81773067,82073217,82073218,and 82003084)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX05)+1 种基金Shanghai Municipal Key Clinical Specialty,CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2 M-5-058)National Key R&D Program of China(2020YFE0202200).
文摘Numerous recent studies have shown that myeloid-derived suppressor cells(MDSCs),a strongly heterogeneous population of immunosuppressive cells,are dysregulated in the presence of many cancers.MDSCs present different phenotypes and play prominent roles in the tumor microenvironment.To date,gene therapies targeting MDSCs are the most innovative and flexible methods to specifically modify the tumor microenvironment.Here,we summarize current studies related to the phenotypes,functions,and mechanisms of MDSCs and explore the therapeutic landscape of chemokines that affect the balance between subpopulations of MDSCs.
文摘Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF).Methods A total of 25 HBV-ACLF patients