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1.
Cell Metab ; 36(6): 1320-1334.e9, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38838643

ABSTRACT

Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.


Subject(s)
Circadian Clocks , Gastrointestinal Microbiome , Myeloid-Derived Suppressor Cells , Animals , Mice , Myeloid-Derived Suppressor Cells/metabolism , Humans , Neoplasm Metastasis , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/microbiology , Mice, Inbred C57BL , Male , Tumor Microenvironment , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Lung Neoplasms/metabolism , Female , Mice, Inbred BALB C , Cell Line, Tumor
2.
J Exp Clin Cancer Res ; 43(1): 157, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38824552

ABSTRACT

Phosphoinositide-3-kinase γ (PI3Kγ) plays a critical role in pancreatic ductal adenocarcinoma (PDA) by driving the recruitment of myeloid-derived suppressor cells (MDSC) into tumor tissues, leading to tumor growth and metastasis. MDSC also impair the efficacy of immunotherapy. In this study we verify the hypothesis that MDSC targeting, via PI3Kγ inhibition, synergizes with α-enolase (ENO1) DNA vaccination in counteracting tumor growth.Mice that received ENO1 vaccination followed by PI3Kγ inhibition had significantly smaller tumors compared to those treated with ENO1 alone or the control group, and correlated with i) increased circulating anti-ENO1 specific IgG and IFNγ secretion by T cells, ii) increased tumor infiltration of CD8+ T cells and M1-like macrophages, as well as up-modulation of T cell activation and M1-like related transcripts, iii) decreased infiltration of Treg FoxP3+ T cells, endothelial cells and pericytes, and down-modulation of the stromal compartment and T cell exhaustion gene transcription, iv) reduction of mature and neo-formed vessels, v) increased follicular helper T cell activation and vi) increased "antigen spreading", as many other tumor-associated antigens were recognized by IgG2c "cytotoxic" antibodies. PDA mouse models genetically devoid of PI3Kγ showed an increased survival and a pattern of transcripts in the tumor area similar to that of pharmacologically-inhibited PI3Kγ-proficient mice. Notably, tumor reduction was abrogated in ENO1 + PI3Kγ inhibition-treated mice in which B cells were depleted.These data highlight a novel role of PI3Kγ in B cell-dependent immunity, suggesting that PI3Kγ depletion strengthens the anti-tumor response elicited by the ENO1 DNA vaccine.


Subject(s)
Vaccines, DNA , Animals , Mice , Vaccines, DNA/pharmacology , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Humans , Cell Line, Tumor , Cancer Vaccines/immunology , Cancer Vaccines/pharmacology , Disease Models, Animal , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism
3.
Commun Biol ; 7(1): 669, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822095

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) play a crucial role in maintaining maternal-fetal tolerance by expressing some immune-suppressive molecules, such as indoleamine 2,3-dioxygenase (IDO). Toxoplasma gondii (T. gondii) infection can break the immune microenvironment of maternal-fetal interface, resulting in adverse pregnancy outcomes. However, whether T. gondii affects IDO expression in dMDSCs and the molecular mechanism of its effect are still unclear. Here we show, the mRNA level of IDO is increased but the protein level decreased in infected dMDSCs. Mechanistically, the upregulation of transcriptional levels of IDO in dMDSCs is regulated through STAT3/p52-RelB pathway and the decrease of IDO expression is due to its degradation caused by increased SOCS3 after T. gondii infection. In vivo, the adverse pregnancy outcomes of IDO-/- infected mice are more severe than those of wide-type infected mice and obviously improved after exogenous kynurenine treatment. Also, the reduction of IDO in dMDSCs induced by T. gondii infection results in the downregulation of TGF-ß and IL-10 expression in dNK cells regulated through Kyn/AhR/SP1 signal pathway, eventually leading to the dysfunction of dNK cells and contributing the occurrence of adverse pregnancy outcomes. This study reveals a novel molecular mechanism in adverse pregnancy outcome induced by T. gondii infection.


Subject(s)
Down-Regulation , Indoleamine-Pyrrole 2,3,-Dioxygenase , Killer Cells, Natural , Toxoplasmosis , Animals , Female , Humans , Mice , Pregnancy , Decidua/immunology , Decidua/metabolism , Decidua/parasitology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Mice, Inbred C57BL , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Toxoplasma/physiology , Toxoplasmosis/immunology , Toxoplasmosis/parasitology
4.
Front Immunol ; 15: 1390327, 2024.
Article in English | MEDLINE | ID: mdl-38742106

ABSTRACT

Introduction: Tuberculous pleural effusion (TPE) stands as one of the primary forms of extrapulmonary tuberculosis (TB) and frequently manifests in regions with a high prevalence of TB, consequently being a notable cause of pleural effusion in such areas. However, the differentiation between TPE and parapneumonic pleural effusion (PPE) presents diagnostic complexities. This study aimed to evaluate the potential of myeloid-derived suppressor cells (MDSCs) in the pleural fluid as a potential diagnostic marker for distinguishing between TPE and PPE. Methods: Adult patients, aged 18 years or older, who presented to the emergency room of a tertiary referral hospital and received a first-time diagnosis of pleural effusion, were prospectively enrolled in the study. Various immune cell populations, including T cells, B cells, natural killer (NK) cells, and MDSCs, were analyzed in both pleural fluid and peripheral blood samples. Results: In pleural fluid, the frequency of lymphocytes, including T, B, and NK cells, was notably higher in TPE compared to PPE. Conversely, the frequency of polymorphonuclear (PMN)-MDSCs was significantly higher in PPE. Notably, compared to traditional markers such as the neutrophil-to-lymphocyte ratio and adenosine deaminase level, the frequency of PMN-MDSCs emerged as a more effective discriminator between PPE and TPE. PMN-MDSCs demonstrated superior positive and negative predictive values and exhibited a higher area under the curve in the receiver operating characteristic curve analysis. PMN-MDSCs in pleural effusion increased the levels of reactive oxygen species and suppressed the production of interferon-gamma from T cells following nonspecific stimulation. These findings suggest that MDSC-mediated immune suppression may contribute to the pathology of both TPE and PPE. Discussion: The frequency of PMN-MDSCs in pleural fluid is a clinically useful indicator for distinguishing between TPE and PPE.


Subject(s)
Biomarkers , Myeloid-Derived Suppressor Cells , Pleural Effusion , Tuberculosis, Pulmonary , Humans , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Male , Female , Pleural Effusion/immunology , Pleural Effusion/diagnosis , Middle Aged , Diagnosis, Differential , Adult , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/immunology , Aged , Pneumonia/diagnosis , Pneumonia/immunology , Prospective Studies , Tuberculosis, Pleural/diagnosis , Tuberculosis, Pleural/immunology
5.
Exp Hematol ; 129: 104125, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38743005

ABSTRACT

The revised International Prognostic Index (R-IPI) is an important prognostic tool in diffuse large B cell lymphoma (DLBCL); however, outcomes can vary markedly within R-IPI groups, and additional prognostic markers are needed. We conducted a prospective observational study to evaluate the circulating immature myeloid (IM) cell subsets and cytokine profiles of 31 patients with newly diagnosed DLBCL before and after chemoimmunotherapy. Among circulating IM cells, myeloid-derived suppressor cells (MDSCs) were the predominant cell type (73.8% ± 26%). At baseline, circulating monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) were predominantly mutually exclusive. Patients with DLBCL clustered into three distinct immunotypes according to MDSC levels and subtype predominance: M-MDSChigh, PMN-MDSChigh, and MDSClow. The M-MDSChigh immunotype was associated with the germinal center B cell-like (GCB) subtype and elevated serum IL-8 and MIP-1α levels. PMN-MDSChigh was associated with the non-GCB subtype and elevated IL-8, MCP-1, IP-10, TNFα, and IL-1Ra levels. Standard chemoimmunotherapy partially reduced M-MDSC distribution across the MDSClow and M-MDSChigh groups. By contrast, among the MDSClow and PMN-MDSChigh groups, PMN-MDSCs persisted after treatment. Two high-risk patients with non-GCB DLBCL and MDSClow immunotype experienced early disease recurrence within 12 months of treatment completion. This study demonstrates that distinct types of MDSCs are associated with subtypes of DLBCL. MDSC levels are dynamic and may be associated with disease status. Persistence of PMN-MDSCs among high-risk patients with DLBCL may be associated with early relapse.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Myeloid-Derived Suppressor Cells , Humans , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/pathology , Myeloid-Derived Suppressor Cells/metabolism , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/blood , Female , Male , Middle Aged , Aged , Prognosis , Inflammation/pathology , Adult , Prospective Studies , Aged, 80 and over , Cytokines/blood , Immunotherapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
6.
Proc Natl Acad Sci U S A ; 121(20): e2306776121, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38709933

ABSTRACT

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.


Subject(s)
Breast Neoplasms , Cell Differentiation , Diet, High-Fat , Disease Progression , Gastrointestinal Microbiome , Leucine , Myeloid-Derived Suppressor Cells , Animals , Diet, High-Fat/adverse effects , Leucine/metabolism , Female , Humans , Mice , Myeloid-Derived Suppressor Cells/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/microbiology , Breast Neoplasms/metabolism , Obesity/microbiology , Obesity/metabolism , Obesity/pathology , Cell Line, Tumor
7.
BMC Gastroenterol ; 24(1): 163, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38745150

ABSTRACT

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


Subject(s)
CD11b Antigen , Liver Cirrhosis , Liver Regeneration , Mice, Inbred C57BL , Myeloid-Derived Suppressor Cells , Animals , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/immunology , Mice , Liver Cirrhosis/pathology , Liver Cirrhosis/metabolism , Liver Regeneration/physiology , CD11b Antigen/metabolism , Male , Disease Models, Animal , Liver/pathology , Liver/metabolism , Vascular Endothelial Growth Factor A/metabolism , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/physiopathology , Concanavalin A , Ligation , Lipopolysaccharides , Interleukin-10/metabolism , Transforming Growth Factor beta/metabolism , Hepatic Stellate Cells/metabolism , Coculture Techniques , Hepatocytes/metabolism , Hepatocytes/pathology , Bile Ducts
8.
Cells ; 13(10)2024 May 07.
Article in English | MEDLINE | ID: mdl-38786019

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) play an essential role in suppressing the antitumor activity of T lymphocytes in solid tumors, thus representing an attractive therapeutic target to enhance the efficacy of immunotherapy. However, the differences in protein expression between MDSCs and their physiological counterparts, particularly polymorphonuclear neutrophils (PMNs), remain inadequately characterized, making the specific identification and targeting of MDSCs difficult. PMNs and PMN-MDSCs share markers such as CD11b+CD14-CD15+/CD66b+, and some MDSC-enriched markers are emerging, such as LOX-1 and CD84. More proteomics studies are needed to identify the signature and markers for MDSCs. Recently, we reported the induced differentiation of isogenic PMNs or MDSCs (referred to as iPMNs and iMDSCs, respectively) from the human promyelocytic cell line HL60. Here, we profiled the global proteomics and membrane proteomics of these cells with quantitative mass spectrometry, which identified a 41-protein signature ("cluster 6") that was upregulated in iMDSCs compared with HL60 and iPMN. We further integrated our cell line-based proteomics data with a published proteomics dataset of normal human primary monocytes and monocyte-derived MDSCs induced by cancer-associated fibroblasts. The analysis identified a 38-protein signature that exhibits an upregulated expression pattern in MDSCs compared with normal monocytes or PMNs. These signatures may provide a hypothesis-generating platform to identify protein biomarkers that phenotypically distinguish MDSCs from their healthy counterparts, as well as potential therapeutic targets that impair MDSCs without harming normal myeloid cells.


Subject(s)
Cell Differentiation , Myeloid-Derived Suppressor Cells , Neutrophils , Proteomics , Humans , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/cytology , Neutrophils/metabolism , Neutrophils/cytology , Proteomics/methods , HL-60 Cells , Cell Line
9.
Med Oncol ; 41(7): 165, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38819590

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting melanoma metastasis. Reprogramming MDSCs into mature M1 macrophages has emerged as a strategy to inhibit metastasis. Decitabine (Dec) is known to eradicate MDSCs and suppress tumor growth. In this study, we provide evidence that Dec not only reduces the MDSC population by inducing apoptosis, arresting cell cycle, and impairing recruitment, but also suppresses their immunosuppressive function by downregulating related genes and facilitating differentiation into M1 macrophages. Transcriptomic analysis of Dec-treated MDSCs revealed a marked downregulation of immunosuppressive genes including S100a9, S100a8, Vegf, Cxcr2, and Nos2. Meanwhile, M1 macrophage-associated genes involved in immune activation were upregulated, such as Ddx58, Isg15, Tap1, Ccl5, Cxcl9, and Cxcl10. Further bioinformatic analysis indicated that Dec promotes MDSC-to-M1 macrophage differentiation and activates innate immune pathways including NOD-like signaling to enhance anti-tumor immunity. Time-course studies implied that Dec upregulates myeloid transcription factor Irf7 to initiate MDSC differentiation and orchestrate the anti-tumor immune response. Collectively, our study unveils a novel dual-functional mechanism of Dec as both a cytotoxic agent reducing MDSCs and an inducer of their differentiation into M1 macrophages, thereby alleviating immunosuppression. This highlights Dec's potential for clinical melanoma metastasis suppression.


Subject(s)
Decitabine , Melanoma , Myeloid-Derived Suppressor Cells , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Animals , Decitabine/pharmacology , Mice , Melanoma/drug therapy , Melanoma/pathology , Melanoma/immunology , Humans , Mice, Inbred C57BL , Cell Differentiation/drug effects , Antimetabolites, Antineoplastic/pharmacology , Cell Line, Tumor , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Apoptosis/drug effects , Immune Tolerance/drug effects
10.
Int J Mol Sci ; 25(10)2024 May 09.
Article in English | MEDLINE | ID: mdl-38791188

ABSTRACT

In our previous studies, a novel cryothermal therapy (CTT) was developed to induce systemic long-term anti-tumor immunity. Natural killer (NK) cells were found to play an important role in CTT-induced long-term immune-mediated tumor control at the late stage after CTT, but the underlying mechanism is unclear. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that have potent immunosuppressive effects on T cells and weaken the long-term benefits of immunotherapy. Consequently, overcoming MDSC immunosuppression is essential for maintaining the long-term efficacy of immunotherapy. In this study, we revealed that NK cells considerably diminish MDSC accumulation at the late stage after CTT, boost T cell production, increase T cell activation, and promote MDSC maturation, culminating in Th1-dominant CD4+ T cell differentiation and enhancing NK and CD8+ T cell cytotoxicity. Additionally, NK cells activate ERK signaling in MDSCs through NKG2D-ligand interaction to increase the activity of tumor necrosis factor (TNF)-α converting enzyme (TACE)-cleaved membrane TNF-α. Furthermore, Increased TACE activity releases more soluble TNF-α from MDSCs to promote MDSC maturation. In our studies, we propose a novel mechanism by which NK cells can overcome MDSC-induced immunosuppression and maintain CTT-induced persistent anti-tumor immunity, providing a prospective therapeutic option to improve the performance of cancer immunotherapy.


Subject(s)
Killer Cells, Natural , Myeloid-Derived Suppressor Cells , NK Cell Lectin-Like Receptor Subfamily K , Tumor Necrosis Factor-alpha , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Mice , Tumor Necrosis Factor-alpha/metabolism , Mice, Inbred C57BL , Lymphocyte Activation/immunology , Cell Differentiation , Ligands , ADAM17 Protein/metabolism
11.
Front Immunol ; 15: 1355405, 2024.
Article in English | MEDLINE | ID: mdl-38720891

ABSTRACT

Introduction: Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. Methods: Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering. Results: We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome. Discussion: The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity.


Subject(s)
Myeloid-Derived Suppressor Cells , Sepsis , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Humans , Sepsis/immunology , Transcriptome , Male , Female , Cell Differentiation/immunology , Gene Expression Profiling
12.
J Nanobiotechnology ; 22(1): 237, 2024 May 12.
Article in English | MEDLINE | ID: mdl-38735920

ABSTRACT

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) promote tumor growth, metastasis, and lead to immunotherapy resistance. Studies revealed that miRNAs are also expressed in MDSCs and promote the immunosuppressive function of MDSCs. Currently, few studies have been reported on inducible cellular microvesicle delivery of nucleic acid drugs targeting miRNA in MDSCs for the treatment of malignant tumors. RESULTS AND CONCLUSION: In this study, we designed an artificial DNA named G-quadruplex-enhanced circular single-stranded DNA-9 (G4-CSSD9), that specifically adsorbs the miR-9 sequence. Its advanced DNA folding structure, rich in tandem repeat guanine (G-quadruplex), also provides good stability. Mesenchymal stem cells (MSCs) were prepared into nanostructured vesicles by membrane extrusion. The MSC microvesicles-encapsulated G4-CSSD9 (MVs@G4-CSSD9) was delivered into MDSCs, which affected the downstream transcription and translation process, and reduced the immunosuppressive function of MDSCs, so as to achieve the purpose of treating melanoma. In particular, it provides an idea for the malignant tumor treatment.


Subject(s)
DNA, Single-Stranded , G-Quadruplexes , Mesenchymal Stem Cells , MicroRNAs , Myeloid-Derived Suppressor Cells , Animals , Myeloid-Derived Suppressor Cells/metabolism , Mice , DNA, Single-Stranded/chemistry , Cell Line, Tumor , Mice, Inbred C57BL , Cell-Derived Microparticles/chemistry , Cell-Derived Microparticles/metabolism , DNA, Circular/chemistry , Humans , Melanoma/drug therapy
13.
J Immunol Res ; 2024: 2765001, 2024.
Article in English | MEDLINE | ID: mdl-38774603

ABSTRACT

ß-Glucan is the main component of the cell wall of pathogen-associated molecular patterns (PAMPs) including various yeast, fungi, or certain bacteria. Previous reports demonstrated that ß-glucan was widely investigated as a potent immunomodulators to stimulate innate and adaptive immune responses, which indicated that it could be recommended as an effective adjuvant in immunotherapy. However, the detailed effects of ß-glucan on neonatal immunity are still largely unknown. Here, we found that ß-glucan did not affect the frequencies and numbers of myeloid cells in the spleen and bone marrow from neonates. Functional assay revealed that ß-glucan from neonates compromised the immunosuppressive function of immature myeloid cells, which were myeloid-derived suppressor cells (MDSCs). Flow cytometry or gene expression analysis revealed that ß-glucan-derived polymorphonuclear (PMN)-MDSCs produced lower level of reactive oxygen species (ROS) and arginase-1 (Arg1) in neonatal mice. Furthermore, ß-glucan administration significantly decreased the frequency and ROS level of PMN-MDSCs in vitro. These observations suggest that ß-glucan facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.


Subject(s)
Animals, Newborn , Arginase , Myeloid-Derived Suppressor Cells , Reactive Oxygen Species , beta-Glucans , beta-Glucans/pharmacology , Animals , Mice , Reactive Oxygen Species/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/drug effects , Arginase/metabolism , Myeloid Cells/metabolism , Myeloid Cells/immunology , Myeloid Cells/drug effects , Spleen/immunology , Spleen/metabolism , Spleen/cytology , Humans , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/drug effects , Mice, Inbred C57BL
14.
Neoplasia ; 53: 101005, 2024 07.
Article in English | MEDLINE | ID: mdl-38761506

ABSTRACT

Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing ApcMin/+ mice with Cul4bΔIEC mice to achieve specific deletion of Cul4b in the gut epithelium against an ApcMin/+ background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited ApcMin/+ adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted ApcMin/+ adenomas. Furthermore, the addition of MDSCs to in vitro cultured ApcMin/+; Cul4bΔIEC adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating ApcMin/+ adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.


Subject(s)
Adenoma , Cullin Proteins , Disease Models, Animal , Myeloid-Derived Suppressor Cells , Animals , Cullin Proteins/genetics , Cullin Proteins/metabolism , Mice , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/pathology , Adenoma/pathology , Adenoma/genetics , Adenoma/metabolism , Adenomatous Polyposis Coli Protein/genetics , Humans , Tumor Microenvironment/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/etiology , Gene Deletion , Intestinal Mucosa/pathology , Intestinal Mucosa/metabolism
16.
Nat Microbiol ; 9(6): 1467-1482, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38750176

ABSTRACT

Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically, P. anaerobius administration activated integrin α2ß1-NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2+ MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC_22, a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally, therapeutic targeting of either integrin α2ß1 or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius-mediated resistance to anti-PD1 therapy in CRC.


Subject(s)
Colorectal Neoplasms , Myeloid-Derived Suppressor Cells , Programmed Cell Death 1 Receptor , Animals , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Mice , Colorectal Neoplasms/immunology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/microbiology , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Humans , Cell Line, Tumor , Integrin alpha2beta1/metabolism , Immune Checkpoint Inhibitors/pharmacology , Signaling Lymphocytic Activation Molecule Family/metabolism , Mice, Inbred C57BL , Signal Transduction , Drug Resistance, Neoplasm , Disease Models, Animal , Female , NF-kappa B/metabolism
17.
Cell Cycle ; 23(5): 602-612, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38717991

ABSTRACT

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


Subject(s)
DNA-(Apurinic or Apyrimidinic Site) Lyase , Granulocyte-Macrophage Colony-Stimulating Factor , Myeloid-Derived Suppressor Cells , Stomach Neoplasms , Stomach Neoplasms/pathology , Stomach Neoplasms/genetics , Stomach Neoplasms/immunology , Stomach Neoplasms/metabolism , Animals , Myeloid-Derived Suppressor Cells/metabolism , Cell Line, Tumor , Humans , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , Mice , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Gene Knockdown Techniques , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Neoplasm Metastasis , Mice, Inbred BALB C , Cytokines/metabolism , Cell Proliferation/genetics
18.
Sci Transl Med ; 16(747): eadi2952, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38748775

ABSTRACT

Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.


Subject(s)
Immune Tolerance , Interleukin-6 , Killer Cells, Natural , Myeloid-Derived Suppressor Cells , STAT3 Transcription Factor , STAT3 Transcription Factor/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Interleukin-6/metabolism , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/immunology , Animals , Humans , Signal Transduction , Tumor Microenvironment/immunology , Mice, Knockout , Cell Line, Tumor , Female , Mice , Mice, Inbred C57BL , Neoplasms/immunology , Neoplasms/pathology
19.
Pharmacol Res ; 204: 107204, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38704109

ABSTRACT

We previously demonstrated that the C-E-cad protein encoded by circ-E-cadherin promotes the self-renewal of glioma stem cells. The expression pattern of C-E-cad in breast cancer and its potential function in the tumor microenvironment are unclear. The expression of circ-E-cadherin and C-E-cad was detected in breast cancer specimens. The influence of C-E-cad expression on MDSCs was assessed using FACS and in vivo tumorigenesis experiments. The synergistic effect of anti-C-E-cad and anti-PD-1 antibodies was validated in vivo. circ-E-cadherin and the encoded protein C-E-cad were found to be upregulated in breast cancer vs. normal samples. C-E-cad promotes the recruitment of MDSCs, especially PMN-MDSCs. C-E-cad activates EGFR signaling in tumor cells and promotes the transcription of CXCL8; moreover, C-E-cad binds to MDSCs and maintains glycolysis in PMN-MDSCs. Targeting C-E-cad enhanced anti-PD-1 efficiency. Our data suggested that C-E-cad is markedly overexpressed in breast cancer and promotes MDSC recruitment and survival. Targeting C-E-cad increases the efficacy of immune checkpoint inhibitor therapy.


Subject(s)
Breast Neoplasms , Cadherins , Myeloid-Derived Suppressor Cells , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Humans , Female , Cadherins/metabolism , Cadherins/genetics , Animals , Tumor Microenvironment/drug effects , Cell Line, Tumor , Mice, Inbred BALB C , Mice , ErbB Receptors/metabolism , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/genetics , Antigens, CD/metabolism , Antigens, CD/genetics , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use
20.
Int J Biol Macromol ; 270(Pt 1): 131949, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38749890

ABSTRACT

Granular ß-1,3-glucan extracted from the wall of Ganoderma lucidum spores, named GPG, is a bioregulator. In this study, we investigated the structural, thermal, and other physical properties of GPG. We determined whether GPG ameliorated immunosuppression caused by Gemcitabine (GEM) chemotherapy. Triple-negative breast cancer mice with GPG combined with GEM treatment had reduced tumor burdens. In addition, GEM treatment alone altered the tumor microenvironment(TME), including a reduction in antitumor T cells and a rise in myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). However, combined GPG treatment reversed the tumor immunosuppressive microenvironment induced by GEM. GPG inhibited bone marrow (BM)-derived MDSC differentiation and reversed MDSC expansion induced by conditioned medium (CM) in GEM-treated E0771 cells through a Dectin-1 pathway. In addition, GPG downgraded PD-L1 and IDO1 expression on MDSC while boosting MHC-II, CD86, TNF-α, and IL-6 expression. In conclusion, this study demonstrated that GPG could alleviate the adverse effects induced by GEM chemotherapy by regulating TME.


Subject(s)
Myeloid-Derived Suppressor Cells , Reishi , Spores, Fungal , Triple Negative Breast Neoplasms , Tumor Microenvironment , beta-Glucans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Animals , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/immunology , Mice , beta-Glucans/pharmacology , beta-Glucans/chemistry , Reishi/chemistry , Female , Tumor Microenvironment/drug effects , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Lectins, C-Type
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