A New Epigenetic Model to Stratify Glioma Patients According to Their Immunosuppressive State.
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ABSTRACT:
SUBMITTER: Polano M
PROVIDER: S-EPMC8001235 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:Aberrant expression of RNA processing genes may drive the alterative RNA profile in lower-grade gliomas (LGGs). Thus, we aimed to further stratify LGGs based on the expression of RNA processing genes. METHODS:This study included 446 LGGs from The Cancer Genome Atlas (TCGA, training set) and 171 LGGs from the Chinese Glioma Genome Atlas (CGGA, validation set). The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was conducted to develop a risk-signature. The receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used to study the prognosis value of the risk-signature. RESULTS:Among the tested 784 RNA processing genes, 276 were significantly correlated with the OS of LGGs. Further LASSO Cox regression identified a 19-gene risk-signature, whose risk score was also an independently prognosis factor (P<0.0001, multiplex Cox regression) in the validation dataset. The signature had better prognostic value than the traditional factors "age", "grade" and "WHO 2016 classification" for 3- and 5-year survival both two datasets (AUCs > 85%). Importantly, the risk-signature could further stratify the survival of LGGs in specific subgroups of WHO 2016 classification. Furthermore, alternative splicing events for genes such as EGFR and FGFR were found to be associated with the risk score. mRNA expression levels for genes, which participated in cell proliferation and other processes, were significantly correlated to the risk score. CONCLUSIONS:Our results highlight the role of RNA processing genes for further stratifying the survival of patients with LGGs and provide insight into the alternative splicing events underlying this role.
| S-EPMC6777941 | biostudies-literature
Project description:Purpose: Multiple studies from last decades have shown that the microenvironment of carcinomas plays an important role in the initiation, progression and metastasis of cancer. Our group has previously identified novel cancer stroma gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of two tumors of fibroblasts as surrogates for physiologic stromal expression patterns. The aim of this study is to find additional new types of tumor stroma gene expression patterns. Results: 53 tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the elastofibroma (EF) and fibroma of tendon sheath (FOTS) gene signatures demonstrated robust outcome results for survival in the four breast cancer datasets. The EF signature positive breast cancers (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature positive breast cancers (11-35% of the cohort) had a worse outcome. The combined stromal signatures of EF, FOTS, and our previously identified DTF, and CSF1 signatures characterize, in part, the stromal expression profile for the tumor microenvironment for between 74%-90% of all breast cancers. Conclusions: We defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis.
2013-11-21 | GSE42948 | GEO
Project description:BackgroundPrior investigations of language functions have focused on the response profiles of particular brain regions. However, the specialized and static view of language processing does not explain numerous observations of functional recovery following brain surgery. To investigate the dynamic alterations of functional connectivity (FC) within language network (LN) in glioma patients, we explored a new flexible model based on the neuroscientific hypothesis of core-periphery organization in LN.MethodsGroup-level LN mapping was determined from 109 glioma patients and forty-two healthy controls (HCs) using independent component analysis (ICA). FC and mean network connectivity (mNC: l/rFCw, FCb, and FCg) were compared between patients and HCs. Correlations between mNC and tumor volume (TV) were calculated.ResultsWe identified ten separate LN modules from ICA. Compared to HCs, glioma patients showed a significant reduction in language network functional connectivity (LNFC), with a distinct pattern modulated by tumor position. Left hemisphere gliomas had a broader impact on FC than right hemisphere gliomas, with more reduced edges away from tumor sites (p=0.011). mNC analysis revealed a significant reduction in all indicators of FC except for lFCw in right hemisphere gliomas. These alterations were associated with TV in a double correlative relationship depending on the tumor position across hemispheres.ConclusionOur findings emphasize the importance of considering the modulatory effects of core-periphery mechanisms from a network perspective. Preoperative evaluation of changes in LN caused by gliomas could provide the surgeon a reference to optimize resection while maintaining functional balance.
| S-EPMC7953055 | biostudies-literature
Project description:Glioma is one of the most common malignant tumors of the central nervous system and is characterized by extensive infiltrative growth, neovascularization, and resistance to various combined therapies. In addition to heterogenous populations of tumor cells, the glioma stem cells (GSCs) and other nontumor cells present in the glioma microenvironment serve as critical regulators of tumor progression and recurrence. In this review, we discuss the role of several resident or peripheral factors with distinct tumor-promoting features and their dynamic interactions in the development of glioma. Localized antitumor factors could be silenced or even converted to suppressive phenotypes, due to stemness-related cell reprogramming and immunosuppressive mediators in glioma-derived microenvironment. Furthermore, we summarize the latest knowledge on GSCs and key microenvironment components, and discuss the emerging immunotherapeutic strategies to cure this disease.
| S-EPMC6308128 | biostudies-literature
Project description:Macrophages (M?s)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of M?s/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated M? inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-?1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of M?/microglia phagocytosis, induction of M?/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-?1, and MIC-1, cytokines known to recruit and polarize the M?s/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the M?/microglia to an M2 phenotype, inhibited M?/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-?1 by the M?s/microglia, and enhanced the capacity of M?s/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive M?s/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.
| S-EPMC3098021 | biostudies-literature
Project description:Purpose: Multiple studies from last decades have shown that the microenvironment of carcinomas plays an important role in the initiation, progression and metastasis of cancer. Our group has previously identified novel cancer stroma gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of two tumors of fibroblasts as surrogates for physiologic stromal expression patterns. The aim of this study is to find additional new types of tumor stroma gene expression patterns. Results: 53 tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the elastofibroma (EF) and fibroma of tendon sheath (FOTS) gene signatures demonstrated robust outcome results for survival in the four breast cancer datasets. The EF signature positive breast cancers (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature positive breast cancers (11-35% of the cohort) had a worse outcome. The combined stromal signatures of EF, FOTS, and our previously identified DTF, and CSF1 signatures characterize, in part, the stromal expression profile for the tumor microenvironment for between 74%-90% of all breast cancers. Conclusions: We defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis. Gene expression profiling by 3SEQ was performed on 8 additional types of fibrous tumors, to identify different fibrous tumor specific gene expression signatures. We then determined the significance of the fibrous tumor gene signatures in four publically available breast cancer datasets (GSE1456, GSE4922, GSE3494, NKI Dataset).
2013-11-21 | E-GEOD-42948 | biostudies-arrayexpress
Project description:Epidemiological studies have indicated significant associations of leukocyte mitochondrial DNA (mtDNA) copy number with risk of several malignancies, including glioma. However, whether mtDNA content can predict the clinical outcome of glioma patients has not been investigated.The mtDNA content of peripheral blood leukocytes from 336 glioma patients was examined using a real-time PCR-based method. Kaplan-Meier curves and Cox proportional hazards regression model were used to examine the association of mtDNA content with overall survival (OS) and progression-free survival (PFS) of patients. To explore the potential mechanism, the immune phenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines from another 20 glioma patients were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively.Patients with high mtDNA content showed both poorer OS and PFS than those with low mtDNA content. Multivariate Cox regression analysis demonstrated that mtDNA content was an independent prognostic factor for both OS and PFS. Stratified analyses showed that high mtDNA content was significantly associated with poor prognosis of patients with younger age, high-grade glioma or adjuvant radiochemotherapy. Immunological analysis indicated that patients with high mtDNA content had significantly lower frequency of natural killer cells in PBMCs and higher plasma concentrations of interleukin-2 and tumour necrosis factor-?, suggesting an immunosuppression-related mechanism involved in mtDNA-mediated prognosis.Our study for the first time demonstrated that leukocyte mtDNA content could serve as an independent prognostic marker and an indicator of immune functions in glioma patients.
| S-EPMC4647544 | biostudies-other
Project description:BACKGROUND:A number of hepatocellular carcinoma (HCC) patients have developed resistance against transcatheter arterial chemoembolization (TACE) treatment. In this study, we aimed to develop a panel of microRNAs (miRs) biomarkers to predict clinical outcomes in HCC patients after TACE treatment. METHODS:The expression level of twenty miRs was evaluated in FFPE tissues collected from 33 HCC patients. We selected four differentially expressed miRs in TACE-responders versus non-responders and re-assessed their expression in 51 serum samples. The expressions of miRs associated with overall survival (OS), progression-free survival (PFS), and treatment outcomes were investigated. The diagnostic accuracy of these miRs in predicting patients' response to TACE was also evaluated. RESULTS:The baseline of miR-106b, miR-107 and miR-133b was significantly elevated (p?<?.001) in sera of TACE-responders while miR-26a was elevated (p?<?.001) in non-responders. miR-26a and miR-133b recorded the highest diagnostic performance as individual classifiers in response to TACE (AUC?=?1.0 and 100% sensitivity and specificity). Intriguingly, miR-133b distinguished complete responders from partial responders and non-responders (AUC???0.90). The PFS was improved (p?<?.05) in the high expression group of miR-31, miR-200b, miR-133b and miR-181a over their low expression group. CONCLUSION:Circulating miR-133b, miR-26a, miR-107 and miR-106 in serum are potential candidates to be utilized as prognostic biomarkers for predication of TACE treatment outcomes in HCC patients.
| S-EPMC6397777 | biostudies-literature
Project description:BackgroundTumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression, and therapy resistance. Specific tools for image-guided analysis of spatiotemporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of fluorodeoxyglucose (18F)DPA-714* (translocator protein [TSPO]) PET-MRI in the assessment of the immunosuppressive TME in glioma patients, and (ii) to cross-correlate imaging findings with in-depth immunophenotyping.MethodsTo characterize the glioma TME, a mixed collective of 9 glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]fluoro-ethyl-tyrosine (FET)-PET-MRI. Image-guided biopsy samples were immunophenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity.ResultsWe found a strong relationship (r = 0.84, P = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to human leukocyte antigen D related-positive (HLA-DR+) activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714-positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution.Conclusion[18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME.
| S-EPMC7339888 | biostudies-literature
Project description:In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent's ability to restore immunological function in the context of intended use.
| S-EPMC7526457 | biostudies-literature