Molecular and Clinical Characterization of LIGHT/TNFSF14 Expression at Transcriptional Level via 998 Samples With Brain Glioma
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ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC8430338 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: PD-L1 has been widely reported as immune check points in a range of malignancies as well as some immune-originated diseases. In glioma, the role of PD-L1 remains unclear. We aimed at investigating its role at transcriptome level and relationship with clinical practice. Method and patients: In total, 976 glioma samples with transcriptome data, including 301 microarray data from Chinese Glioma Genome Atlas (CGGA project) and 675 RNAseq data from TCGA project, were enrolled into our study. Clinical and IDH mutation data were also available. R language was used as the main tool for statistical analysis and graphical work. Results: PD-L1 expression was found to be positively correlated with WHO grade of glioma. PD-L1 seemed to express more in mesenchymal subtype according to TCGA transcriptional classification scheme and may contribute as a potential marker for mesenchymal subtype in glioblastoma. Pearson correlation test indicated that PD-L1 showed robust correlation with PD1, PD-L2, and CD80 in CGGA dataset. Subsequent gene ontology analysis based on significantly correlated genes of PD-L1 revealed that PD-L1 seemed to be profoundly associated with T cell activation. To further investigate the relationship between PD-L1 expression and immune response, we selected a series of immune signatures, which were then transformed into metagenes, and found that PD-L1 expression was particularly paralleled with T-cells and macrophages-related immune response instead of B cell linage-related immune response. In line with the corresponding biological process, PD-L1 exhibited predictive value for glioma patients: Higher PD-L1 indicated significantly shorter survival, especially in glioblastoma. Conclusion: PD-L1 is upregulated in glioblastoma, and is synergistic with other check point members. Moreover, PD-L1 is significantly associated with T-cell activation and macrophage-related immune response and predicts much worse survival for patients, warranting clinical trials of PD1/PD-L1 checkpoint inhibitors for potential glioma treatment.
| S-EPMC5139638 | biostudies-literature
Project description:BackgroundGlioma is the most common and aggressive type of primary brain tumor in adults. Although radiotherapy and chemotherapy are used in the treatment of glioma, survival remains unsatisfactory. Chemoresistance is one of the primary reasons for the poor prognosis of glioma. Several studies have demonstrated that glioma stem cells (GSC) may be one of the reasons for chemoresistance. In this article, we attempt to search for a new biomarker related to GSC and chemoresistance in glioma.MethodsWe used three datasets (GSE23806, COSMIC, and CGGA) to search for the genes related to GSC, temozolomide (TMZ) resistance, and overall survival. The selected gene was investigated with respect to the relationship between mRNA levels and clinical characteristics in the CGGA and TCGA dataset. Gene ontology (GO) analysis was used for bioinformatics analysis. Kaplan-Meier survival analysis and Cox regression analysis were used for survival analysis.ResultsThe transmembrane protein 71 (TMEM71) gene was selected for further research. TMEM71 was highly expressed in GSCs and TMZ-resistant cells. The TMEM71 mRNA levels increased with increasing grades of glioma. In IDH-wild-type and MGMT-unmethylated samples, TMEM71 was overexpressed. The TMEM71 transcript levels were also increased significantly in mesenchymal subtype gliomas. GO analysis demonstrated that TMEM71 was related to the immune and inflammatory responses, cell proliferation, cell migration, chemotaxis, and the response to drugs. Specifically, PD-1, PD-L1, TIM-3, and B7-H3 were tightly associated with TMEM71 expression. This result indicates that TMEM71 may play an important role in the immune response. More importantly, high expression of TMEM71 was correlated with short survival time in both glioma and glioblastoma patients.ConclusionIn summary, TMEM71 expression was increased in GBM and associated with immune response. Our study suggests that TMEM71 may function as an oncogene and serve as a new effective therapeutic target for the treatment of glioma.
| S-EPMC6698980 | biostudies-literature
Project description:Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.
| S-EPMC4284554 | biostudies-literature
Project description:Glioma is the most common primary malignant brain tumor with limited treatment options and poor prognosis. To investigate the potential relationships between transcriptional characteristics and clinical phenotypes, we applied weighted gene co-expression network analysis (WGCNA) to construct a free-scale gene co-expression network yielding four modules in gliomas. Turquoise and yellow modules were positively correlated with the most malignant glioma subtype (IDH-wildtype glioblastomas). Of them, genes in turquoise module were mainly involved in immune-related terms and were regulated by NFKB1, RELA, SP1, STAT1 and STAT3. Meanwhile, genes in yellow module mainly participated in cell-cycle and division processes and were regulated by E2F1, TP53, E2F4, YBX1 and E2F3. Furthermore, 14 genes in turquoise module were screened as hub genes. Among them, five prognostic hub genes (TNFRSF1B, LAIR1, TYROBP, VAMP8, and FCGR2A) were selected to construct a prognostic risk score model via LASSO method. The risk score of this immune-related gene signature is associated with clinical features, malignant phenotype, and somatic alterations. Moreover, this signature showed an accurate prediction of prognosis across different clinical and pathological subgroups in three independent datasets including 1619 samples. Our results showed that the high-risk group was characterized by active immune-related activities while the low-risk group enriched in neurophysiological-related pathway. Importantly, the high-risk score of our immune signature predicts an enrichment of glioma-associated microglia/macrophages and less response to immune checkpoint blockade (ICB) therapy in gliomas. This study not only provides new insights into the molecular pathogenesis of glioma, but may also help optimize the immunotherapies for glioma patients.
| S-EPMC8654825 | biostudies-literature
Project description:In recent years, research on glioma immunotherapy have grown rapidly. However, the autoimmune-like side effects that are caused by blocking immunological checkpoints hinder their clinical application in gliomas currently. Galectin-9, a ligand for T-cell immunoglobulin mucin 3, has shed a new light on the treatment of malignant glioma. However, the potential mechanism of Galectin-9 is still under discussion. In this study, first, we methodically gathered 1,027 glioma patients with RNA-seq and 986 patients with survival data to explore the role and mechanism of Galectin-9 in gliomas. Second, we analyzed glioma samples from 50 patients in the Department of Neurosurgery, Tianjin Medical University General Hospital. Finally, we found that Galectin-9 was strongly upregulated in glioblastoma multiforme compared with normal brain tissues and lower-grade glioma. Patients with Galectin-9 overexpression had a significantly shorter overall survival. Moreover, the tissue microarray data displayed that the expression of Galectin-9 in the core of tumor is higher than that in the border and was correlated with the shorter survival in glioma patients. Galectin-9 is more highly expressed in the mesenchymal subtype of glioblastoma multiforme than in the other subtypes. Simultaneously, Galectin-9 was closely associated with the immune response and lymphocyte activation, especially T-cell activation. To further determine the underlying role of Galectin-9 in the immune response, we selected seven immune metagenes. Through cluster analysis and correlation analysis, we discovered that Galectin-9 was highly correlated with immune checkpoint molecules and M2 tumor-associated macrophages. In summary, Galectin-9 serves as a potential therapeutic target to treat glioblastoma multiforme.
| S-EPMC7028024 | biostudies-literature
Project description:Background: Researches on immunotherapy of glioma has been increasing exponentially in recent years. However, autoimmune-like side effects of current immune checkpoint blockade hindered the clinical application of immunotherapy in glioma. The discovery of the TIM-3, a tumor-specific immune checkpoint, has shed a new light on solution of this dilemma. We aimed at investigating the role of TIM-3 at transcriptome level and its relationship with clinical practice in glioma. Methods: A cohort of 325 glioma patients with RNA-seq data from Chinese Glioma Genome Atlas (CGGA project) was analyzed, and the results were well validated in TCGA RNA-seq data of 699 gliomas. R language was used as the main tool for statistical analysis and graphical work. Results: TIM-3 was enriched in glioblastoma (the most malignant glioma) and IDH-wildtype glioma. TIM-3 can act as a potential marker for mesenchymal molecular subtype according to TCGA transcriptional classification scheme in glioma. TIM-3 was closely related to immune functions in glioma, especially T cell mediated immune response to tumor cell and T cell mediated cytotoxicity directed against tumor cell target. Moreover, TIM-3 and PD-L1 played almost exactly the same inflammatory activation functions in glioma. Clinically, high expression of TIM-3 was an independent indicator of poor prognosis. Conclusion: The expression of TIM-3 is closely related to the pathology and molecular pathology of glioma. Meanwhile, in glioma TIM-3 plays a specific role in T cell tumor immune response. Therefore, TIM-3 is a promising target for immunotherapeutic strategies, providing an alternative treatment when glioma gains resistance to antibodies of PD-1/PD-L1.
| S-EPMC5593703 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is a common central neural system malignant tumor among adults. Alongside its microscopic spread, immunosuppression in the tumor microenvironment also induces its refractoriness, which makes immunotherapy for GBM particularly important. Unfortunately, traditional immune checkpoint inhibitors (ICIs) often show limited therapeutic effects in GBM clinical trials, and new therapeutic strategies or targets are urgently needed. TNFSF14/LIGHT is a novel immune checkpoint molecule that plays essential roles in both innate and acquired immunity. Despite recent advances in our understanding of the function of TNFSF14/LIGHT in a variety of cancer types, the clinical and immunological importance of TNFSF14/LIGHT in human gliomas has not been fully explained. Here, we employed a comprehensive in silico analysis with publicly available data to analyze the molecular and immune characteristics of TNFSF14/LIGHT to explore its feasibility as an immunotherapy target. Totally, 2215 glioma cases were enrolled in the current study. Immunohistochemistry staining based on patient tissues (n = 34) was performed for the validation. TNFSF14/LIGHT was expressed higher in higher-WHO-grade gliomas and mesenchymal subtypes, and it was sensitive as a prognostic marker in GBM and low-grade glioma (LGG). A nomogram prognostic model was established based on TNFSF14/LIGHT expression together with other risk factors. Additionally, Gene Ontology and pathway analysis revealed that TNFSF14/LIGHT participated in T-cell activities and inflammatory processes. Moreover, analysis based on the structure and interactions of TNFSF14/LIGHT revealed its mutation sites in tumors as well as crucial interacting proteins. Analysis of IMvigor210 indicated the role of TNFSF14/LIGHT in immunotherapy. Altogether, our results reveal an underlying role of TNFSF14/LIGHT as an immunotherapy target in GBM.
| S-EPMC9632349 | biostudies-literature
Project description:BackgroundTumour necrosis factor superfamily protein 14 (TNFSF14), also called LIGHT, is an important regulator of immunological and fibrosis diseases. However, its specific involvement in cardiac fibrosis and atrial fibrillation (AF) has not been fully elucidated. The objective of this study is to examine the influence of LIGHT on the development of myocardial fibrosis and AF.MethodsPCR arrays of peripheral blood mononuclear cells (PBMCs) from patients with AF and sinus rhythm was used to identify the dominant differentially expressed genes, followed by ELISA to evaluate its serum protein levels. Morphological, functional, and electrophysiological changes in the heart were detected in vivo after the tail intravenous injection of recombinant LIGHT (rLIGHT) in mice for 4 weeks. rLIGHT was used to stimulate bone marrow-derived macrophages (BMDMs) to prepare a macrophage-conditioned medium (MCM) in vitro. Then, the MCM was used to culture mouse cardiac fibroblasts (CFs). The expression of relevant proteins and genes was determined using qRT-PCR, western blotting, and immunostaining.ResultsThe mRNA levels of LIGHT and TNFRSF14 were higher in the PBMCs of patients with AF than in those of the healthy controls. Additionally, the serum protein levels of LIGHT were higher in patients with AF than those in the healthy controls and were correlated with left atrial reverse remodelling. Furthermore, we demonstrated that rLIGHT injection promoted macrophage infiltration and M2 polarisation in the heart, in addition to promoting atrial fibrosis and AF inducibility in vivo, as detected with MASSON staining and atrial burst pacing respectively. RNA sequencing of heart samples revealed that the PI3Kγ/SGK1 pathway may participate in these pathological processes. Therefore, we confirmed the hypothesis that rLIGHT promotes BMDM M2 polarisation and TGB-β1 secretion, and that this process can be inhibited by PI3Kγ and SGK1 inhibitors in vitro. Meanwhile, increased collagen synthesis and myofibroblast transition were observed in LIGHT-stimulated MCM-cultured CFs and were ameliorated in the groups treated with PI3Kγ and SGK1 inhibitors.ConclusionLIGHT protein levels in peripheral blood can be used as a prognostic marker for AF and to evaluate its severity. LIGHT promotes cardiac fibrosis and AF inducibility by promoting macrophage M2 polarisation, wherein PI3Kγ and SGK1 activation is indispensable.
| S-EPMC10424430 | biostudies-literature
Project description:The expression and function of CD163 in glioma are not fully understood. In this report, we collected totally 1323 glioma samples from the Chinese Glioma Genome Atlas (CGGA) dataset, including 325 RNA-seq data and 301 mRNA microarray data, and 697 glioma samples from The Cancer Genome Atlas (TCGA) dataset to characterize the molecular and clinical features of CD163 in glioma by conducting a large-scale study. We found that CD163 expression was positively associated with the grade of malignancy of glioma. CD163 expression was up-regulated in IDH wild-type glioma and mesenchymal subtype. Gene ontology analysis suggested that CD163-related genes were more involved in immune response and angiogenesis in glioma. Moreover, CD163 showed a positive relationship with stromal and immune cell populations. Kaplan-Meier curves analysis revealed that higher CD163 expression indicated significantly poor survival in glioma and glioblastoma multiforme (GBM). Pearson correlation analysis revealed that CD163 was robustly associated with the immune checkpoints and other macrophage markers. These results demonstrated that CD163 predicts poor prognosis in glioma patients. Additionally, combination of CD163 and immune checkpoints may impair angiogenesis and reverse dysfunctional phenotypes of T cells, which suggest that CD163 may be a promising biomarker and target for immunotherapeutic strategies. Abbreviations: CGGA: Chinese Glioma Genome Atlas; TCGA: The Cancer Genome Atlas; TAMs: Tumor associated macrophages; IDH: isocitrate dehydrogenase; GBM: glioblastoma.
| S-EPMC6527268 | biostudies-literature
Project description:ImportanceConclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1).ObservationsThis assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%-99%) and 100% specificity (95% CI, 95%-100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe.Conclusions and relevanceThe genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations.
| S-EPMC4872045 | biostudies-literature