Dataset Information

Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

ABSTRACT: BACKGROUND:Immunotherapies targeting glioblastoma (GBM) have led to significant improvements in patient outcomes. TOX is closely associated with the immune environment surrounding tumors, but its role in gliomas is not fully understood. METHODS:Using data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we analyzed the transcriptomes of 1691 WHO grade I-IV human glioma samples. The R language was used to perform most of the statistical analyses. Somatic mutations and somatic copy number variation (CNV) were analyzed using GISTIC 2.0. RESULTS:TOX was down-regulated in malignant gliomas compared to low grade gliomas, and upregulated in the proneural and IDH mutant subtypes of GBM. TOXlow tumours are associated with the loss of PTEN and amplification of EGFR, while TOXhigh tumours harbor frequent mutations in IDH1 (91%). TOX was highly expressed in leading edge regions of tumours. Gene ontology and pathway analyses demonstrated that TOX was enriched in multiple immune related processes including lymphocyte migration in GBM. Finally, TOX had a negative association with the infiltration of several immune cell types in the tumour microenvironment. CONCLUSION:TOX has the potential to be a new prognostic marker for GBM.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7409670 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

Zhang Hao H Fan Fan F Yu Yuanqiang Y Wang Zeyu Z Liu Fangkun F Dai Ziyu Z Zhang Liyang L Liu Zhixiong Z Cheng Quan Q

Journal of translational medicine 20200806 1

<h4>Background</h4>Immunotherapies targeting glioblastoma (GBM) have led to significant improvements in patient outcomes. TOX is closely associated with the immune environment surrounding tumors, but its role in gliomas is not fully understood.<h4>Methods</h4>Using data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we analyzed the transcriptomes of 1691 WHO grade I-IV human glioma samples. The R language was used to perform most of the statistical analyses. Soma ...[more]

PMID: 32762688

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Project description:BackgroundThymocyte selection-associated high mobility group box (TOX) plays a crucial role on the development of innate immunity and tumor microenvironment. This study aims to explore the prognostic potential of TOX and comprehensively analyze the correlations between TOX, immune infiltration, and T cells function in diverse cancers particularly lung adenocarcinoma (LUAD).MethodsTIMER was used to analyze TOX expression in different cancers. Potential prognostic value of TOX was evaluated by the PrognoScan, Kaplan-Meier Plotter, and GEPIA2. The relationships between TOX, immune infiltration, and related gene marker sets were analyzed by TIMER and GEPIA2. Single-cell RNA-seq for T cells in LUAD was analyzed to further investigate the correlations between TOX expression and different T cells populations.ResultsTOX downregulates in most of the cancer types and correlates with poor prognosis in LUAD. TOX shows significant impacts on survival of LUAD with early stage, ever-smoking, or low-TMB status. Increased TOX expression positively correlates with high immune infiltration levels in most of the immune cells and functional T cells including exhausted T cells. Moreover, multiple key genes of exhausted T cells comprising PD-1, TIM-3, TIGHT, and CXCL13 have remarkable interaction with TOX. Specifically, TOX is observed with high enrichment in exhausted CD4+ and CD8+ T cells populations in single-cell RNA-seq analysis for LUAD.ConclusionTOX is a prognosis-related biomarker for multiple cancer types especially LUAD. Increased TOX expression significantly increase immune infiltration levels in most of the immune cells comprising CD8+ T cells, CD4+ T cells, mast cells, and functional T cells. Moreover, we verified that TOX highly correlates with exhausted T cells and is probable a critical regulator promoted T cells exhaustion in LUAD. Detection of TOX expression could help to predict prognosis and regulating TOX expression in exhausted T cells may offer a novel strategy in maximizing immunotherapy efficacy for LUAD.

Project description:The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in nontumoral brain (NB) and grade I-IV gliomas. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (GBMs) that excluded long-survivor cases expressed higher levels of RSK1 (RSK1hi ). No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2hi ) were associated with worse survival. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBM demonstrating the lowest RSK3 protein levels. RSK1hi and, to a lesser extent, RSK2hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform-specific peculiarities. The progression-dependent expression and association with immune infiltration suggest RSK1 as a potential progression marker and therapeutic target for gliomas.

Project description:Certain glioma subtypes, such as glioblastoma multiforme or low-grade glioma, are common malignant intracranial tumors with high rates of relapse and malignant progression even after standard therapy. The overall survival (OS) is poor in patients with gliomas; hence, effective prognostic prediction is crucial. Herein, the present study aimed to explore the potential role of hypoxia-inducible factor 1 subunit alpha (HIF1α) in gliomas and investigate the association between HIF1α and infiltrating immune cells in gliomas. Data from The Cancer Genome Atlas were evaluated via RNA sequencing, clinicopathological, immunological checkpoint, immune infiltration and functional enrichment analyses. Validation of protein abundance was performed using paraffin-embedded samples from patients with glioma. A nomogram model was created to forecast the OS rates at 1, 3 and 5 years after cancer diagnosis. The association between OS and HIF1α expression was estimated using Kaplan-Meier survival analysis and the log-rank test. Finally, HIF1α expression was validated using western blotting, reverse transcription-quantitative PCR, Cell Counting Kit-8 and Transwell assays. The results demonstrated that HIF1α expression was significantly upregulated in gliomas compared with normal human brain glial cells. Immunohistochemistry staining demonstrated differential expression of the HIF1α protein. Moreover, glioma cell viability and migration were inhibited via HIF1α downregulation. HIF1α impacted DNA replication, cell cycling, DNA repair and the immune microenvironment in glioma. HIF1α expression was also positively associated with several types of immune cells and immunological checkpoints and with neutrophils, plasmacytoid dendritic cells and CD56bright cells. The Kaplan-Meier survival analyses further demonstrated a strong association between high HIF1α expression and poor prognosis in patients with glioma. Analysis of the receiver operating characteristic curves demonstrated that HIF1α expression accurately differentiated paired normal brain cells from tumor tissues. Collectively, these findings suggested the potential for HIF1α to be used as a novel prognostic indicator for patients with glioma and that OS prediction models may help in the future to develop effective follow-up and treatment strategies for these patients.

Dataset Information

Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

Publications

Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

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