Glioma Immunotherapy Research Articles

Identification of cuproptosis-related lncRNAs for prognosis and immunotherapy in glioma.

Glioma is a highly invasive primary brain tumour, making it challenging to accurately predict prognosis for glioma patients. Cuproptosis is a recently discovered cell death attracting significant attention in the tumour field. Whether cuproptosis-related genes have prognostic predictive value has not been clarified. In this study, uni-/multi-variate Cox and Lasso regression analyses were applied to construct a risk model based on cuproptosis-related lncRNAs using TCGA and CGGA cohorts. A nomogram was constructed to quantify individual risk, including clinical and genic characteristics and risk. GO and KEGG analyses were used to define functional enrichment of DEGs. Tumour mutation burden (TMB) and immune checkpoint analyses were performed to evaluate potential responses to ICI therapy. Ten prognostic lncRNAs were obtained from Cox regression. Based on the median risk score, patients were divided into high- and low-risk groups. Either for grade 2-3 or for grade 4, glioma patients with high-risk exhibited significant poorer prognoses. The risk was an independent risk factor associated with overall survival. The high-risk group was functionally associated with immune responses and cancer-related pathways. The high-risk group was associated with higher TMB scores. The expression levels of many immune checkpoints in the high-risk group were significantly higher than those in the low-risk group. Differentiated immune pathways were primarily enriched in the IFN response, immune checkpoint and T-cell co-stimulation pathways. In conclusion, we established a risk model based on cuproptosis-related lncRNAs showing excellent prognostic prediction ability but also indicating the immuno-microenvironment status of glioma.

Identification of tumor-associated antigens and immune subtypes of lower-grade glioma and glioblastoma for mRNA vaccine development

BackgroundmRNA became a promising therapeutic approach in many diseases. This study aimed to identify the tumor antigens specifically expressed in tumor cells for lower-grade glioma (LGG) and glioblastoma (GBM) patients.MethodsIn this work, the mRNA microarray expression profile and clinical data were obtained from 301 samples in the Chinese Glioma Genome Atlas (CGGA) database, the mRNA sequencing data and clinical data of 701 samples were downloaded from The Cancer Genome Atlas (TCGA) database. Genetic alterations profiles were extracted from CGGA and cBioPortal datasets. R language and GraphPad Prism software were applied for the statistical analysis and graph work.ResultsPTBP1 and SLC39A1, which were overexpressed and indicated poor prognosis in LGG patients, were selected as tumor-specific antigens for LGG patients. Meanwhile, MMP9 and SLC16A3, the negative prognostic factors overexpressed in GBM, were identified as tumor-specific antigens for GBM patients. Besides, three immune subtypes (LGG1-LGG3) and eight WGCNA modules were identified in LGG patients. Meanwhile, two immune subtypes (GBM1–GBM2) and 10 WGCNA modules were selected in GBM. The immune characteristics and potential functions between different subtypes were diversity. LGG2 and GBM1 immune subtype were associated with longer overall survival than other subtypes.ConclusionIn this study, PTBP1 and SLC39A1 are promising antigens for mRNA vaccines development in LGG, and MMP9 and SLC16A3 were potential antigens in GBM. Our analyses indicated that mRNA vaccine immunotherapy was more suitable for LGG2 and GBM1 subtypes. This study was helpful for the development of glioma immunotherapies.

Comprehensive characterization of TNFSF14/LIGHT with implications in prognosis and immunotherapy of human gliomas.

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.

Prognostic value of cuproptosis-related genes signature and its impact on the reshaped immune microenvironment of glioma.

Glioma is the most prevalent malignancy in the central nervous system. The impact of ion-induced cell death on malignant tumors’ development and immune microenvironment has attracted broad attention in recent years. Cuproptosis is a novel copper-dependent mechanism that could potentially regulate tumor cell death by targeting mitochondria respiration. However, the role of cuproptosis in gliomas remains unclear. In the present study, we investigated the relationships between the expression of cuproptosis-related genes (CRGs) and tumor characteristics, including prognosis and microenvironment of glioma, by analyzing multiple public databases and our cohort. Consensus clustering based on the expression of twelve CRGs stratified the glioma patients into three subgroups with significantly different prognosis and immune microenvironment landscapes. Reduced immune infiltration was associated with the less aggressive CRG cluster. A prognostic CRGs risk signature (CRGRS), based on eight critical CRGs, classified the patients into low- and high-risk groups in the training set and was endorsed by validation sets from multiple cohorts. The high-risk group manifested a shorter overall survival, and further survival analysis demonstrated that the CRGRS was an independent prognostic factor. The nomogram combining CRGRS and other clinicopathological factors exhibited good accuracy in predicting the prognosis of glioma patients. Moreover, analyses of tumor immune microenvironment indicated that higher CRGRS was correlated with increased immune cell infiltration but diminished immune function. Gliomas in the high-risk group exhibited higher expression of multiple immune checkpoints, including PD-1 and PD-L1, and a better predicted therapy response to immune checkpoint inhibitors. In conclusion, our study elucidated the connections between CRGs expression and the aggressiveness of gliomas, and the application of CRGRS derived a new robust model for prognosis evaluation of glioma patients. The correlations between the profiles of CRGs expression and immune tumor microenvironment illuminated prospects and potential indications of immunotherapy for glioma.

Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma.

Hypoxic microenvironment is immunosuppressive and protumorigenic, and elevated lactate is an intermediary in the modulation of immune responses. However, as critical lactate transporters, the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated. Gene expression in low- and high-grade glioma (LGG and GBM) was evaluated with TCGA database. The TISIDB, TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints. Compared with normal tissues, a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM, and closely related to the poor prognosis only in LGG. Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflammation in glioma. The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis. TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells, which was correlated to tumor-associated macrophages and neutrophils that are immunosuppressive. SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints (especially PD1, PD-L1, PD-L2, Tim-3) and immunosuppressive factors (TGF-β andIL-10) in glioma. Furthermore, SLC16A3 had a positive correlation to activation markers of tumor-associated neutrophils and chemokines such as CCL2, CCL22, CXCR2, CXCR4 in LGG and CCL7, CCL20 CXCL8 in GBM, which could enhance infiltration of immunosuppressive cells to the tumor microenvironment. In general, our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immunosuppressive cell infiltration, which contributes to immune evasion and a worse prognosis in glioma. Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.

DNA methylation regulator-mediated modification patterns and tumor microenvironment characterization in glioma.

Growing evidences indicate DNA methylation plays a crucial regulatory role in inflammation, innate immunity, and immunotherapy. However, the overall landscape of various DNA methylation regulatory genes and their relationship with the infiltration of immune cells into the tumor microenvironment (TME) as well as the response to immunotherapy in gliomas is still not clear. Therefore, we comprehensively analyzed the correlation between DNA methylation regulator patterns, infiltration of immune cell-types, and tumor immune response status in gather glioma cohorts. Furthermore, we calculated the DNA methylation score (DMS) for individual glioma samples, then evaluated the relationship between DMS, clinicopathological characteristics, and overall survival (OS) in patients with gliomas. Our results showed three distinct DNA methylation regulator patterns among the glioma patients which correlated with three distinct tumor immune response phenotypes, namely, immune-inflamed, immune-excluded, and immune desert. We then calculated DMS for individual glioma samples based on the expression of DNA methylation-related gene clusters. Furthermore, DMS, tumor mutation burden (TMB), programmed death 1 (PD-1) expression, immune cell infiltration status in the TME, and Tumor Immune Dysfunction and Exclusion (TIDE) scores were associated with survival outcomes and clinical responses to immune checkpoint blockade therapy. We also validated the predictive value of DMS in two independent immunotherapy cohorts. In conclusion, our results demonstrated that three DNA methylation regulator patterns that correlated with three tumor immune response phenotypes. Moreover, we demonstrated that DMS was an independent predictive biomarker that correlated with survival outcomes of glioma patients and their responses to immunotherapy therapeutic regimens.

Development of immunotherapy for high-grade gliomas: Overcoming the immunosuppressive tumor microenvironment.

The preclinical and clinical development of novel immunotherapies for the treatment of central nervous system (CNS) tumors is advancing at a rapid pace. High-grade gliomas (HGG) are aggressive tumors with poor prognoses in both adult and pediatric patients, and innovative and effective therapies are greatly needed. The use of cytotoxic chemotherapies has marginally improved survival in some HGG patient populations. Although several challenges exist for the successful development of immunotherapies for CNS tumors, recent insights into the genetic alterations that define the pathogenesis of HGG and their direct effects on the tumor microenvironment (TME) may allow for a more refined and targeted therapeutic approach. This review will focus on the TME in HGG, the genetic drivers frequently found in these tumors and their effect on the TME, the development of immunotherapy for HGG, and the practical challenges in clinical trials employing immunotherapy for HGG. Herein, we will discuss broadly the TME and immunotherapy development in HGG, with a specific focus on glioblastoma multiforme (GBM) as well as additional discussion in the context of the pediatric HGG diagnoses of diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG).

ADAMDEC1 accelerates GBM progression via activation of the MMP2-related pathway.

The ADAM (a disintegrin and metalloprotease) gene-related family including ADAM, ADAMTS, and ADAM-like decysin-1 has been reported to play an important role in the pathogenesis of multiple diseases, including cancers (lung cancer, gliomas, colorectal cancer, and gastrointestinal cancer). However, its biological role in gliomas remains largely unknown. Here, we aimed to investigate the biological functions and potential mechanism of ADAMDEC1 in gliomas. The mRNA and protein expression levels of ADAMDEC1 were upregulated in glioma tissues and cell lines. ADAMDEC1 showed a phenomenon of “abundance and disappear” expression in gliomas and normal tissues in that the higher the expression of ADAMDEC1 presented, the higher the malignancy of gliomas and the worse the prognosis. High expression of ADAMDEC1 was associated with immune response. Knockdown of ADAMDEC1 could decrease the proliferation and colony-forming ability of LN229 cells, whereas ADAMDEC1 overexpression has opposite effects in LN229 cells in vitro. Furthermore, we identified that ADAMDEC1 accelerates GBM progression via the activation of the MMP2 pathway. In the present study, we found that the expression levels of ADAMDEC1 were significantly elevated compared with other ADAMs by analyzing the expression levels of ADAM family proteins in gliomas. This suggests that ADAMDEC1 has potential as a glioma clinical marker and immunotherapy target.

Identification of Prognostic Signature of Necroptosis-Related lncRNAs and Molecular Subtypes in Glioma.

Background In tumor progression and epigenetic regulation, long non-coding RNA (lncRNA) and necroptosis are crucial regulators. However, in glioma microenvironment, the role of necroptosis-related lncRNAs (NRLs) remains unknown. Method In this study, the RNA-seq and clinical annotation of glioma patients were analyzed using the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. To investigate prognosis and tumor microenvironment of NRLs in gliomas, we conducted a prediction model based on the training cohort. The accuracy of the model was verified in the verification cohort. Results A signature composed of 13 NRLs was identified, and all glioma patients were divided into two groups. We found that each group has unique survival outcomes, biological behaviors, and immune infiltrating status. The necroptosis-related lncRNA signature (NRLS) model was found to be an independent risk factor in multivariate Cox analysis. Immunosuppressive microenvironment was positively correlated with the high-risk group. Due to significantly different IC50 between risk groups, NRLS could be used as a guide for chemotherapeutic treatment. Further, the entire cohort was divided into two clusters depending on NRLs. Consensus clustering method and the risk scoring system were basically similar. Survival probability was higher in Cluster 2, while Cluster 1 has stronger immunologic infiltration. Conclusion The predictive signature could be a prognostic factor independently and serve to detect the role of NRLs in glioma immunotherapy response.

Identification and validation of roles of lysyl oxidases in the predictions of prognosis, chemotherapy and immunotherapy in glioma.

Background: Previous investigations have illustrated that lysyl oxidase family enzymes (LOXs) are contributing factors for tumor progression and remodeling immunomicroenvironment. However, it is scarce regarding comprehensive analysis of LOXs in the predictions of prognosis, chemotherapy and immunotherapy in glioma, the highly invasive brain tumor. Our present work aimed to explore the prognostic value, chemotherapeutic drug sensitivity and immunotherapy according to distinct LOXs expressions in glioma through bioinformatics analysis and experimental verification. Methods: We collected gene expression data and clinical characteristics from the public databases including Chinese Glioma Genome Atlas (CGGA)-325, CGGA-693, the Cancer Genome Atlas (TCGA), IMvigor210 and Van Allen 2015 cohorts. The correlations between the clinicopathological factors and differential LOXs expressions were analyzed. The ROC curve and Kaplan-Meier analysis were conducted to evaluate the prediction ability of prognosis. Chemotherapeutic drug sensitivity via distinct LOXs expression levels was predicted using the pRRophetic package. Immune score, immune cell infiltration and immune checkpoint expression levels were also analyzed through diverse algorithms in R software. Finally, mRNA and protein expressions of LOXs were validated in glioma cells (T98G and A172) by real-time quantitative PCR and Western blot, respectively. Results: Our results demonstrated that high levels of LOXs expressions were positively associated with glioma grades, older age and MGMT unmethylated status while elevations of LOXs were negatively correlated with IDH mutation or 1p/19q co-deletion. Furthermore, the glioma patients with low levels of LOXs also exhibited better prognosis. Also, differential LOXs expressions were associated with at least 12 chemotherapeutic drug sensitivity. Besides, it was also found that glioma patients with high LOXs expressions showed higher enrichment scores for immune cell infiltration and increased levels of immune checkpoints, suggesting the critical role of distinct LOXs expression levels for glioma immunotherapy. The predictive roles of LOXs expression in tumor immunotherapy were also validated in two immunotherapy cohorts including IMvigor 210 and Van Allen 2015. Experimental results revealed that expressions of LOX, LOXL1, LOXL2, and LOXL3 were higher in glioma cell lines at mRNA and protein levels. Conclusion: Our findings altogether indicate that LOXs have potent predictive value for prognosis, chemotherapy and immunotherapy in glioma patients.

Dual role of pseudogene TMEM198B in promoting lipid metabolism and immune escape of glioma cells.

Dysregulation of pseudogenes, enhancement of fatty acid synthesis and formation of immunosuppressive microenvironment are important factors that promote the malignant progression of glioma. It is of great significance to search for the molecular mechanism of interaction between the three and then perform targeted interference for improving the treatment of glioma. In this study, we found that pseudogene transmembrane protein 198B (TMEM198B) was highly expressed in glioma tissues and cell lines, and it could promote malignant progression of glioma by regulating lipid metabolism reprogramming and remodeling immune microenvironment. Applying the experimental methods of gene interference, lipidomics and immunology, we further confirmed that TMEM198B promoted PLAG1 like zinc finger 2 (PLAGL2) expression by mediating tri-methylation of histone H3 on lysine 4 (H3K4me3) of PLAGL2 through binding to SET domain containing 1B (SETD1B). Increased PLAGL2 could transcriptional activate ATP citrate lyase (ACLY) and ELOVL fatty acid elongase 6 (ELOVL6) expression, and then influenced the biological behaviors of glioma cells via enhancing the de novo lipogenesis and fatty acid acyl chain elongation. At the same time, TMEM198B promoted macrophages lipid accumulation and intensification of fatty acid oxidation (FAO) through glioma-derived exosomes (GDEs), further induced macrophages to M2 polarization, which subsequently facilitated immune escape of glioma cells. In conclusion, our present study clarifies that the TMEM198B/PLAGL2/ACLY/ELOVL6 pathway conducts crucial regulatory effects on the malignant progression of glioma, which provides novel targets and new ideas for molecular targeted therapy and immunotherapy of glioma.

A novel chemokine-based signature for prediction of prognosis and therapeutic response in glioma.

Gliomas are the primary malignant brain tumor and characterized as the striking cellular heterogeneity and intricate tumor microenvironment (TME), where chemokines regulate immune cell trafficking by shaping local networks. This study aimed to construct a chemokine-based gene signature to evaluate the prognosis and therapeutic response in glioma. In this study, 1024 patients (699 from TCGA and 325 from CGGA database) with clinicopathological information and mRNA sequencing data were enrolled. A chemokine gene signature was constructed by combining LASSO and SVM-RFE algorithm. GO, KEGG, and GSVA analyses were performed for function annotations of the chemokine signature. Candidate mRNAs were subsequently verified through qRT-PCR in an independent cohort including 28 glioma samples. Then, through immunohistochemical staining (IHC), we detected the expression of immunosuppressive markers and explore the role of this gene signature in immunotherapy for glioma. Lastly, the Genomics of Drug Sensitivity in Cancer (GDSC) were leveraged to predict the potential drug related to the gene signature in glioma. A constructed chemokine gene signature was significantly associated with poorer survival, especially in glioblastoma, IDH wildtype. It also played an independent prognostic factor in both datasets. Moreover, biological function annotations of the predictive signature indicated the gene signature was positively associated with immune-relevant pathways, and the immunosuppressive protein expressions (PD-L1, IBA1, TMEM119, CD68, CSF1R, and TGFB1) were enriched in the high-risk group. In an immunotherapy of glioblastoma cohort, we confirmed the chemokine signature showed a good predictor for patients' response. Lastly, we predicted twelve potential agents for glioma patients with higher riskscore. In all, our results highlighted a potential 4-chemokine signature for predicting prognosis in glioma and reflected the intricate immune landscape in glioma. It also threw light on integrating tailored risk stratification with precision therapy for glioblastoma.

Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma.

BackgroundPyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas.MethodsThe TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated.ResultsPatients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas.ConclusionThe pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.

ABCD3 is a prognostic biomarker for glioma and associated with immune infiltration: A study based on oncolysis of gliomas.

BackgroundGliomas are the most lethal primary brain tumors and are still a major therapeutic challenge. Oncolytic virus therapy is a novel and effective means for glioma. However, little is known about gene expression changes during this process and their biological functions on glioma clinical characteristics and immunity.MethodsThe RNA-seq data after oncolytic virus EV-A71 infection on glioma cells were analyzed to screen significantly downregulated genes. Once ABCD3 was selected, The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Genotype-Tissue Expression (GTEx), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) data were used to analyze the relationship between ABCD3 expression and clinical characteristics in glioma. We also evaluated the influence of ABCD3 on the survival of glioma patients. CIBERSORT and Tumor Immune Estimation Resource (TIMER) were also used to investigate the correlation between ABCD3 and cancer immune infiltrates. Gene set enrichment analysis (GSEA) was performed to functionally annotate the potential functions or signaling pathways related to ABCD3 expression.ResultsABCD3 was among the top 5 downregulated genes in glioma cells after oncolytic virus EV-A71 infection and was significantly enriched in several GO categories. Both the mRNA and protein expression levels of ABCD3 were upregulated in glioma samples and associated with the prognosis and grades of glioma patients. The Kaplan–Meier (K-M) curve analysis revealed that patients with high ABCD3 expression had shorter disease-specific survival (DSS) and overall survival (OS) than those with low ABCD3 expression. Moreover, ABCD3 expression could affect the immune infiltration levels and diverse immune marker sets in glioma. A positive correlation was found between ABCD3 and macrophages and active dendritic cells in the microenvironment of both the GBM and LGG. Gene sets including the plk1 pathway, tyrobp causal network, ir-damage and cellular response, and interleukin-10 signaling showed significant differential enrichment in the high ABCD3 expression phenotype.ConclusionOur results suggested that ABCD3 could be a potential biomarker for glioma prognosis and immunotherapy response and also further enriched the theoretical and molecular mechanisms of oncolytic virus treatment for malignant gliomas.

A B7-CD28 Family-Based Signature Demonstrates Significantly Different Prognosis and Immunological Characteristics in Diffuse Gliomas.

The B7-CD28 gene family plays a crucial role in modulating immune functions and has served as potential targets for immunotherapeutic strategies. Therefore, we systematically analyzed B7-CD28 family gene expression profiles and constructed a B7-CD28 family-based prognostic signature to predict survival and immune host status in diffuse gliomas. The TCGA dataset was used as a training cohort, and three CGGA datasets (mRNAseq_325, mRNAseq_693 and mRNA-array) were employed as validation cohorts to intensify the findings that we have revealed in TCGA dataset. Ultimately, we developed a B7-CD28 family-based signature that consisted of CD276, CD274, PDCD1LG2 and CD80 using LASSO Cox analysis. This gene signature was validated to have significant prognostic value, and could be used as a biomarker to distinguish pathological grade and IDH mutation status in diffuse glioma. Additionally, we found that the gene signature was significantly related to intensity of immune response and immune cell population, as well as several other important immune checkpoint genes, holding a great potential to be a predictive immune marker for immunotherapy and tumor microenvironment. Finally, a B7-CD28 family-based nomogram was established to predict patient life expectancy contributing to facilitate personalizing therapy for tumor sufferers. In summary, this is the first mathematical model based on this gene family with the aim of providing novel insights into immunotherapy for diffuse glioma.

Characterization of Fatty Acid Metabolism-Related Genes Landscape for Predicting Prognosis and Aiding Immunotherapy in Glioma Patients.

Glioma is a highly malignant brain tumor with a poor survival rate. The involvement of fatty acid metabolism in glioma was examined to find viable treatment options. The information was gathered from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. A prognostic signature containing fatty acid metabolism-dependent genes (FAMDs) was developed to predict glioma outcome by multivariate and most minor absolute shrinkage and selection operator (LASSO) regression analyses. In the TCGA cohort, individuals with a good score had a worse prognosis than those with a poor score, validated in the CGGA cohort. According to further research by “pRRophetic” R package, higher-risk individuals were more susceptible to crizotinib. According to a complete study of the connection between the predictive risk rating model and tumor microenvironment (TME) features, high-risk individuals were eligible for activating the immune cell-associated receptor pathway. We also discovered that anti-PD-1/PD-L1 and anti-CTLA4 immunotherapy are more effective in high-risk individuals. Furthermore, we demonstrated that CCNA2 promotes glioma proliferation, migration, and invasion and regulates macrophage polarization. Therefore, examining the fatty acid metabolism pathway aids our understanding of TME invasion properties, allowing us to develop more effective immunotherapies for glioma.

Immune response to primary glioblastoma

Immunotherapy is a promising and rapidly developing method of therapy patients with different oncological pathology. Considering the demonstrated efficacy in the treatment of patients with some solid tumors, as well as low survival rates and the absence of a significant effect in the standard treatment of most patients with glioblastomas, the question of the use of immunotherapy for malignant gliomas of the brain was raised. However, to decision this problem, it is necessary to consider the interaction of the immune system with tumors of this group. The modern view of the interaction of immunity and glioblastoma is presented. Special attention is paid to the mechanisms of tumor escape and suppression of the functional activity of immune system. The current immunotherapeutic approaches in the treatment of patients with glioblastoma are presented. Interaction of glioblastoma with immune system at all the stages of tumor growth is a complex process. While planning the immunotherapy of this pathology its necessary to take into consideration all mechanisms used by the tumor cells to avoid the immune response and suppress it. However, the clinical studies of this type of therapy proved to be less successful than expected. Further detailed studies of immune-resistance and escape of gliobloastoma must contribute to working out more effective immunotherapy tactics.

ApoE-mediated systemic nanodelivery of granzyme B and CpG for enhanced glioma immunotherapy.

The response of malignant glioma to immunotherapy remains gloomy due to its discrete immunological environment and poor brain penetration of immunotherapeutic agents. Here, we disclose that ApoE peptide-mediated systemic nanodelivery of granzyme B (GrB) and CpG ODN co-stimulates enhanced immunotherapy of murine malignant LCPN glioma model. ApoE peptide-functionalized polymersomes encapsulating GrB (ApoE-PS-GrB) could effectively penetrate the blood-brain barrier-mimicking endothelial cell monolayer in vitro and further be taken up by LCPN cells, inducing strong immunogenic cell death (ICD). The co-administration of ApoE-PS-GrB and ApoE-PS-CpG in orthotopic LCPN glioma-bearing mice co-stimulated cytokine production, maturation of dendritic cells (DCs), infiltration of cytotoxic T lymphocytes (CTLs) while reduction of regulatory T lymphocytes (Treg) and M2 phenotype macrophages in the tumor microenvironment, leading to greatly delayed tumor progression and significantly prolonged survival time compared with all controls. The ApoE-mediated systemic nanodelivery of GrB and CpG ODN opens a new pathway for potent immunotherapy of malignant glioma.

Comprehensive Characterization of a Novel E3-Related Gene Signature With Implications in Prognosis and Immunotherapy of Low-Grade Gliomas.

Gliomas, a type of primary brain tumor, have emerged as a threat to global mortality due to their high heterogeneity and mortality. A low-grade glioma (LGG), although less aggressive compared with glioblastoma, still exhibits high recurrence and malignant progression. Ubiquitination is one of the most important posttranslational modifications that contribute to carcinogenesis and cancer recurrence. E3-related genes (E3RGs) play essential roles in the process of ubiquitination. Yet, the biological function and clinical significance of E3RGs in LGGs need further exploration. In this study, differentially expressed genes (DEGs) were screened by three differential expression analyses of LGG samples from The Cancer Genome Atlas (TCGA) database. DEGs with prognostic significance were selected by the univariate Cox regression analysis and log-rank statistical test. The LASSO-COX method was performed to identify an E3-related prognostic signature consisting of seven genes AURKA, PCGF2, MAP3K1, TRIM34, PRKN, TLE3, and TRIM17. The Chinese Glioma Genome Atlas (CGGA) dataset was used as the validation cohort. Kaplan–Meier survival analysis showed that LGG patients in the low-risk group had significantly higher overall survival time than those in the high-risk group in both TCGA and CGGA cohorts. Furthermore, multivariate Cox regression analysis revealed that the E3RG signature could be used as an independent prognostic factor. A nomogram based on the E3RG signature was then established and provided the prediction of the 1-, 3-, and 5-year survival probability of patients with LGGs. Moreover, DEGs were analyzed based on the risk signature, on which function analyses were performed. GO and KEGG analyses uncovered gene enrichment in extracellular matrix–related functions and immune-related biological processes in the high-risk group. GSEA revealed high enrichment in pathways that promote tumorigenesis and progression in the high-risk group. Furthermore, ESTIMATE algorithm analysis showed a significant difference in immune and stroma activity between high- and low-risk groups. Positive correlations between the risk signature and the tumor microenvironment immune cell infiltration and immune checkpoint molecules were also observed, implying that patients with the high-risk score may have better responses to immunotherapy. Overall, our findings might provide potential diagnostic and prognostic markers for LGG patients and offer meaningful insight for individualized treatment.

Ferroptosis in Glioma Immune Microenvironment: Opportunity and Challenge.

Glioma is the most common intracranial malignant tumor in adults and the 5-year survival rate of glioma patients is extremely poor, even in patients who received Stupp treatment after diagnosis and this forces us to explore more efficient clinical strategies. At this time, immunotherapy shows great potential in a variety of tumor clinical treatments, however, its clinical effect in glioma is limited because of tumor immune privilege which was induced by the glioma immunosuppressive microenvironment, so remodeling the immunosuppressive microenvironment is a practical way to eliminate glioma immunotherapy resistance. Recently, increasing studies have confirmed that ferroptosis, a new form of cell death, plays an important role in tumor progression and immune microenvironment and the crosstalk between ferroptosis and tumor immune microenvironment attracts much attention. This work summarizes the progress studies of ferroptosis in the glioma immune microenvironment.