Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MiRNA expression profiles of peripheral monocytes and glioblastoma-infiltrating macrophages

ABSTRACT: MicroRNAs (miRNAs) are non-coding molecules involved in post-transcriptional gene regulation that have been shown to modulate tumor cell proliferation and apoptosis and to act as oncogenes or tumor-suppressor genes. Although miRNAs have been linked to tumor progression, the connection between tumor-mediated immune modulation and miRNAs has yet to be explored. Specifically, how the miRNA dysregulation affects the monocyte-derived glioblastoma-infiltrating macrophages, the most abundant immune cell population within the glioblastoma microenvironment, and their immune suppressive properties has not been evaluated to date. Here we managed to purify the glioblastoma-infiltrating macrophages from the tumor microenvironment and compared their miRNA expression profile with the matched peripheral monocytes from the peripheral blood of the same GBM patient as well as with healthy donors. Of note, several most down-regulated miRNA candidates revealed in this study, including miR-142-3p, were also known for their role in mediating tumor-associated immunosuppression. These results suggest a novel approach to identify miRNA immune therapeutics using a two-step process: 1) screen miRNA expression from tumor-associated immune cells relative to normal immune cell, and 2) select and prioritize potential candidates on the basis of binding to immunosuppressive pathways or mechanisms. In the study presented here, 12 samples, including peripheral monocyte samples from 4 healthy donors, peripheral monocytes from 4 GBM patients and matched tumor-infiltrating macrophages extracted from the glioblastoma microenvironment, were used to acquire the miRNA expression profiles of 1732 unique mature miRNA sequences via the Phalanx Human miRNA OneArray Microarray v3 Platform.

ORGANISM(S): Homo sapiens

SUBMITTER: Amy Heimberger

PROVIDER: E-GEOD-51332 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma.

Xu Shuo S Wei Jun J Wang Fei F Kong Ling-Yuan LY Ling Xiao-Yang XY Nduom Edjah E Gabrusiewicz Konrad K Doucette Tiffany T Yang Yuhui Y Yaghi Nasser K NK Fajt Virginia V Levine Jonathan M JM Qiao Wei W Li Xin-Gang XG Lang Frederick F FF Rao Ganesh G Fuller Gregory N GN Calin George A GA Calin George A GA Heimberger Amy B AB

Journal of the National Cancer Institute 20140628 8

<h4>Background</h4>The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.<h4>Methods</h4>An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142 ...[more]

PMID: 24974128

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Project description:Tumor-Infiltrating Lymphocytes (TILs) are composed by several immune subpopulations including NK, NKT, Tab, Tgd and B cells. Although some of these cells can have antitumoral activities, there is also a large number of cells which are not tumor-specific,known as bystander cells. These cells may not have a direct role in the antitumoral response but could lead to a modulation of the immune response after time. Recent studies have described fatal encephalitis and myocarditis in cancer patients after immune checkpoint therapies, in which EBV-specific T cells may be involved. Since EBV is able to infect B cells and epithelial cells, both present in the primary tumor site, the first events of these fatal responses could be a consequence of a dysregulation of the immune system in the tumor microenvironment, although this have not been deeply studied. Thus, the main objectives of this study are (i) to use EBV-transformed B cells from the tumor site as a model to study the tumor-infiltrating EBV+ B cells and (ii) to use these EBV-derived B cells to study the relationship with autologous T cells isolated from the tumor site. T cells from TILs have been isolated from a triple negative breast cancer patient before neoadjuvancy and were expanded directly from the biopsy. A Patient-Derived Xenograft (PDX) generated from the breast tumor, progressed into a lymphocytic neoplasm. EBVtransformed B cells were obtained from this PDX (PDX-derived B cells). T Cell Receptor high-throughput sequencing has been used to monitor the clonotypes present in the different samples. We have found 43 clonotypes infiltrating the PDX-562 tissue and 18 of them were also present in the human biopsy or in the biopsy-derived T cell cultures. 5 of these sequences were found in one of the biopsy-derived T cells analyzed. Thus, PDXderived B cells have been used as antigen presenting cells to expand these cells. Few clonotypes were obtained after expansions, although the analysis of the middle CDR3 have revealed a similar pattern with the 18 sequences from the PDX sample. Furthermore, peptides presented by HLA have been eluted from PDX-derived B cells, followed by MS analysis. Peptides obtained derived from 31 different proteins and >40% are cancerrelated in terms of expression.

Project description:Background: Newer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterise extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.Methods: Primary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterisation was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analysed by high-resolution mass spectrometry.Results: We observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR- 323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.Conclusion: Our results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.

Dataset Information

MiRNA expression profiles of peripheral monocytes and glioblastoma-infiltrating macrophages

Publications

Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma.

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