Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA986219 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME), which limits the effects of immunotherapy. This study aims to investigate the immunomodulatory effects of intraperitoneal administration of IL-33 on PM-associated TIME. Immunocompetent mice were used to investigate the role of IL-33 in development of abdominal dissemination and host outcome. Murine (m) and human (h) gastric cancer cells were tested for their response to IL-33 by qRT-PCR, flow cytometry, and immunofluorescence. Survival was significantly prolonged in patients with high Il-33 mRNA expression. Intraperitoneal administration of IL-33 could induce the celiac inflammatory environment, activate immunologic effector cells and reverse the immunosuppressive tumor microenvironment, which delayed tumor progression and peritoneal metastasis of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 (GATA3) signaling pathway. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) showed synergistic anti-tumor effect. Intraperitoneal administration of IL-33 inducing local inflammatory milieu provided a novel approach for the treatment of metastatic peritoneal malignancies, which combined with TAMs reprogramming to reshape TIME could achieve better treatment efficacy.
2023-06-30 | GSE235526 | GEO
Project description:Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33 on PM-associated TIME. Immunocompetent mice were used to investigate the role of IL-33 in development of abdominal dissemination and host outcome. Murine (m) and human (h) gastric cancer cells were tested for their response to IL-33 using qRT-PCR, flow cytometry, and immunofluorescence. The survival was significantly prolonged in patients with high IL-33 mRNA expression. Intraperitoneal administration of IL-33 could induce the celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 (GATA3) signaling pathway. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) showed a synergistic antitumor effect. Intraperitoneal administration of IL-33 inducing local inflammatory milieu provided a novel approach for treating metastatic peritoneal malignancies, which was combined with TAM reprogramming to reshape TIME to achieve better treatment efficacy.
| S-SCDT-10_15252-EMMM_202217321 | biostudies-other
Project description:Mouse peritoneal macrophages were transfected with 80-120 nM miRIDIAN miRNA mimics (miR-mimic-33/miR-mimic-33*) or with 80-120 nM miRIDIAN miRNA inhibitors (anti-miR-33 ASO/anti-miR-33*ASO) Control samples were treated with an equal concentration of a non-targeting control mimics sequence (control mimic) or inhibitor negative control sequence (control aso), to control for non-specific effects in miRNA experiments.
2016-04-18 | GSE79055 | GEO
Project description:Purpose: Previous work has demonstrated that miR-33 is an important regulator of lipid metabolism and atherogenesis. By performing bone marrow transplant experiments into LDLR-/- mice, our work demonstrates that the effects of miR-33 in macrophages play a major role in its ability to reduced atherosclerotic plaque burdon. To have performed extensive additional characterization of the effects of miR-33 deficiency in macrophages icluding RNA-seq analysis of peritoneal macrophages from wildtype, miR-33-/-, LDLR-/-, and miR33-/-/LDLR-/- animals. Methods: Thioglycolate elicited peritoneal macrophages from WT and miR-33-/- mice were harvested by peritoneal lavage. Cells were then plated for 2hr, then washed to remove non-adherant cells. Macrophages were then scraped, pelleted and frozen at -80◦C. Total RNA from WT and miR-33-/- thioglycollate-elicited peritoneal macrophages was extracted and purified using a RNA isolation Kit (Qiagen) followed by DNAse treatment to remove genomic contamination using RNA MinElute Cleanup (Qiagen). The purity and integrity of total RNA sample was verified using the Agilent Bioanalyzer (Agilent Technologies, Santa Clara, CA). rRNA was depleted from RNA samples using Ribo-Zero rRNA Removal Kit (Illumina). RNA libraries from WT BMDMs were performed TrueSeq Small RNA Library preparation (Illumina) and were sequenced for 45 cycles on Illumina HiSeq 2000 platformm (1 x 75bp read length). The reads obtained from the sequencer are trimmed for quality using in-house developed scripts. The trimmed reads are aligned to the reference genome using TopHat2. The transcript abundances and differences calculated using cuffdiff. The results were plotted using R and cummeRbund using in-house developed scripts. Results: Our RNA-seq analysis has allowed us to identify genes and pathways that are altered in miR-33 deficient peritoneal macrophages under hyperlipidemic conditions (LDLR-/- vs. miR33-/-/LDLR-/-). Further analysis of gene expression changes that occur between wildtype and LDLR-/- animals has allowed us to identify which of these changes are likely due to differences in lipid loading and which are independent of these effects.
2018-02-13 | GSE103133 | GEO
Project description:Peritoneal carcinomatosis is a frequent finding in patients with primary gastric cancer, and it is associated with a poor prognosis. A major mechanism in peritoneal carcinomatosis is the dissemination of cancer cells into the abdominal cavity, mainly in diffuse gastric adenocarcinoma. The features that enable diffuse primary gastric tumours to develop peritoneal dissemination have been little investigated and are only incompletely understood. We therefore compared the gene expression profile in patients with diffuse primary gastric cancer with and without peritoneal carcinomatosis. Specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated using oligonucleotide microarrays. Keywords: Disease state analysis
2008-01-31 | GSE8657 | GEO
Project description:Objective Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. Design The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination, was assessed using the YTN16 peritoneal dissemination tumor model mice. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A JAK inhibitor (JAKi) was introduced based on the pathway analysis results. Results Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8+ T cells. However, in mice resistant to dual ICI treatment, even with CD8+ T cell infiltration, most of the T cells exhibited exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the JAK-STAT pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8+ T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. Conclusion Dual ICI treatment exerts its anti-tumor effects by increasing tumor- specific CD8+ T cell infiltration, and the addition of JAKi further improves ICI resistant by reshaping the immunosuppressive TME.
2024-05-28 | GSE250238 | GEO
Project description:Gastric cancer peritoneal metastases (GCPM) is a leading cause of GC-related death. Early detection of GCPM is critical for improving the prognosis of advanced GC. Differentially expressed genes (DEGs) were identified in the GSE62254 database to distinguish between GCPM and non-GCPM. The gastric cancer peritoneal metastases signature (GCPMs) was developed using DEGs. We analysed the effectiveness of GCPMs as indicators for prognosis, chemotherapy, and immune therapy response in GC patients. Subsequently, we analysed the correlation between GCPMs and immune microenvironment as well as immune escape in GC patients. Random forest model and immunohistochemistry was utilized to identify the crucial genes that can aid in the diagnosis of GCPM. We identified five DEGs and utilized their expression to construct GCPMs. Patients with high GCPMs had a higher likelihood of a poor prognosis, while those with low GCPMs appeared to potentially benefit more from chemotherapy. GCPMs were a dependable marker for predicting the response to immunotherapy. Additionally, GCPMs was found to be significantly linked to stromal score and cancer-associated fibroblasts. SYNPO2 has been identified as the gene with the highest significance in the diagnosis of GCPM. Immunohistochemistry suggests that SYNPO2-positive expression in tumour cells, fibroblasts, inflammatory cell may be associated with promoting peritoneal metastasis in GC. GCPMs have shown to be a promising biomarker for predicting the prognosis and response of GC patients to chemotherapy and immunotherapy. The use of GCPMs for individual tumour evaluation may pave the way for personalized treatment for GC patients in the future.
| S-EPMC10660625 | biostudies-literature
Project description:miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.
2021-02-11 | PXD023471 | Pride
Project description:miR-33 is an intronic miRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve HDL biogenesis in the liver and increase circulating HDL-C levels in both rodents and non-human primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole body miR-33 knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver, and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardio-metabolic diseases.
2021-01-31 | GSE164517 | GEO
Project description:Rationale: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome and atherosclerosis. The in vivo efficacy of current anti-miRNAs technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. Objective: To explore the application of anti-miR-33 (miR-33-5p) conjugated pH Low-Insertion Peptides (pHLIP) constructs for the specific targeting of macrophages located in vascular lesions in the regression of atherosclerosis. Methods and Results: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaques macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single cell RNA sequencing analysis revealed higher expression of fibrotic genes (Col2a1, Col3a1, Col1a2, Fn1, etc) and tissue inhibitor of metalloproteinase 3 (Timp3), and downregulation of matrix metallopeptidase 12 (Mmp12) in macrophages from atherosclerotic lesions targeted by pHLIP- anti-miR-33. Conclusions: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoids the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
2022-02-28 | GSE191220 | GEO