The Glioma-Infiltrating T Cell Receptor Repertoire
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79338 | GEO | 2016/05/18
SECONDARY ACCESSION(S): PRJNA315543
REPOSITORIES: GEO
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Project description:While immune signaling has emerged as a defining feature of the glioma microenvironment, local selection of responding T cells and their anti-tumor potential as a population are difficult to measure directly in patients. High-throughput sequencing of T cell receptor repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. Here, we define new immunophenotypes in glioma based on TCRseq and RNA-Seq of tumor tissue, non-neoplastic brain tissue, and peripheral blood from patients. Using information theory, we characterize antigen-driven selection in glioma and its relationship with the expression of distinct immune-functional pathways in the tumor microenvironment. Finally, we identify a strong relationship between usage of certain TCR in peripheral blood and the divergence of the infiltrating T cell population from the peripheral repertoire. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to anti-glioma vaccines and immunotherapy. We characterized the T cell receptor (TCR) repertoires of 11 high-grade glioma patients, three low-grade glioma patients, and thee non-glioma patients by TCRseq of brain-infiltrating T cells and matching peripheral blood. In addition, we obtained gene expression profiles from brain tissue of each patient by RNA-Seq. We additionally measured the TCR repertoires exclusively from peripheral blood of one additional non-glioma patient.
2016-05-18 | E-GEOD-79338 | biostudies-arrayexpress
Project description:Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, cognitive deficits, and seizures, as well as potentially driving glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via ‘Ribotag’, morphometric analysis, and intravital imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden on excitatory neuronal pathophysiology as well as the impact of mTOR inhibition on these neuronal alterations. The Ribotag analysis of peritumoral excitatory neurons showed an upregulation in transcripts encoding for F-actin binding and other dendritic spine-enriched proteins. Light and electron microscopy analyses revealed marked decreases in dendritic spine density in peritumoral neurons. Intravital two-photon imaging in peritumoral excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single neuron level, throughout tumor growth. Intravital two-photon imaging also revealed altered stimulus-evoked somatic calcium activity, both in rate and temporal alignment, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a mTORC1 and mTORC2 inhibitor reversed the translational effect of glioma on neurons, increased dendritic spine density, and functional neuronal alterations. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma – manifested by alterations in ribosome-bound mRNA, dendritic spine morphology, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that peritumoral neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing foundational knowledge for developing therapies targeting neuronal signaling in glioma.
2024-01-30 | GSE254007 | GEO
Project description:Characterizing the tumor microenvironment at the molecular level is essential for understanding the mechanisms of tumorigenesis and evolution. However, the specificity of the blood proteome in localized region of the tumor and its linkages with other systems is difficult to investigate. Here, we propose a spatially multidimensional comparative proteomics strategy using glioma as an example. The blood proteome signature of tumor microenvironment was specifically identified by in situ collection of arterial and venous blood from the glioma region of the brain for comparison with peripheral blood. And by integrating with different dimensions of tissue and peripheral blood proteomics, the information on the genesis, migration and exchange of glioma-associated proteins was revealed, which provided a powerful method for tumor mechanism research and biomarker discovery. The study recruited multidimensional clinical cohorts, allowing the proteomic results to corroborate each other, reliably revealing biological processes specific to gliomas and identifying highly accurate biomarkers.
2023-07-20 | PXD043970 |
Project description:Glioma represents a serious health burden in terms of morbidity and mortality. The prognostic significance of the lymphoid and myeloid infiltrates in glioma is not clearly determined. Moreover, the characterization of different leukocyte subsets in the tumor microenvironment relies mainly on immunohistochemistry observations, and data about their association with prognosis are contradictory. Here, we performed acomprehensive study of both the tumor-infiltrating and circulating immune compartments of patients with high-grade glioma. We identified prognostic tumor and peripheral immune signatures, which associate increased inflammation, immune infiltration and activation with shorter overall survival in high-grade glioma patients. Importantly, we confirmed our observations by flow cytometry analysis and validated the tumor-signature using the TCGA dataset. In addition, both tumor genotype and grade associated with the degree of glioma immune infiltration. Unlike in the majority of cancers, lymphocyte infiltration at the tumor site is anegative prognostic factor in glioma, suggesting the ambivalent pro-tumorigenic role of immune responses in glioma.
2021-11-16 | GSE188812 | GEO
Project description:The role of brain immune compartments in glioma evolution remains elusive. We profiled immune cells in glioma microenvironment and the matched peripheral blood from 11 patients at a single-cell level. Notably, glioblastoma exhibits specific infiltration of certain blood-originated monocytes expressing EGFR ligands including EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (P = 0.019), while co-occurring with mesenchymal subtype (P = 4.7x10-7) and marking worse prognosis (P = 0.004 and 0.032 in two independent cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveals remarkable association between elevated TAMo and glioma mesenchymal transformation. Further analysis identifies FOSL2 as a master regulator of TAMo. The roles of FOSL2-EREG/AREG-EGFR signaling axis in promoting glioma invasion were verified experimentally. Collectively, we have identified TAMo in tumor microenvironment and revealed its driving role in activating EGFR signaling to shape glioma evolution.
2023-08-01 | GSE237779 | GEO
Project description:We performed spatial transcriptome profiling (ST-seq) on nine fresh frozen tissue sections to understand the immunophenotypes; immune cell types, states and their spatial location within the clear cell renal cell carcinoma (ccRCC) tumour microenvironment (TME).
2023-08-16 | E-MTAB-12767 | biostudies-arrayexpress
Project description:Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Previous work shows that tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells. In these analyses, mouse models of glioma have been used to understand the biology of this disease and the therapeutic response, including the biology of the radiation response. We present here an analysis of combined SP and single-cell RNA sequencing of genetically-engineered mouse models of glioma to show a time course of cellular response to radiation. We identify and characterize two distinct tumor cell populations that are inherently radioresistant. In addition, we identify and characterize distinct effects of radiation on immune cell populations within the tumor microenvironment.
2020-07-21 | GSE142168 | GEO
Project description: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.
2014-09-23 | E-GEOD-51332 | biostudies-arrayexpress
Project description:Solid cancers develop within a supportive microenvironment that promotes tumor formation and continued growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically-engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), previous studies have demonstrated that microglia are important for glioma formation and maintenance. To identify the tumor-associated microglial factors that support glioma growth (gliomagens), we employed a comprehensive large scale discovery effort using optimized advanced RNA-sequencing methods. Candidate gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative RT-PCR and RNA FISH following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, Ccl5 was identified as a highly expressed chemokine in both genetically engineered Nf1 mouse and human optic gliomas. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, Ccl5 inhibition with neutralizing antibodies reduced Nf1 mouse optic glioma growth in vivo. Collectively, these findings establish Ccl5 as critical stromal growth factor in low-grade glioma maintenance relevant to future microglia-targeted therapies for brain tumors.
2016-08-17 | GSE65831 | GEO
Project description:Background: Glioblastoma multiform is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after their diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves may directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish clear molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during GBM disease progression. Methods: Using In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We also employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAV and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model. Results: Using a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed that TDECs exist, and that these cells contribute to vessels within the tumor. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and that both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogenous populations are also present in human glioma. Conclusions: Our findings show extensive endothelial cell heterogeneity within the tumor and tumor microenvironment, and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.
2021-01-17 | GSE158700 | GEO