Multi-omics and pharmacological characterization of patient-derived glioma cell lines.

Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma.

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

PTBP1-mediated repression of neuron-specific CDC42 splicing constitutes a genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype glioblastoma.

Gene co-expression networks may encode hitherto inadequately recognized vulnerabilities for adult gliomas. By identifying evolutionally conserved gene co-expression modules around EGFR (EM) or PDGFRA (PM), we recently proposed an EM/PM classification scheme, which assigns IDH-wildtype glioblastomas (GBM) into the EM subtype committed in neural stem cell compartment, IDH-mutant astrocytomas and oligodendrogliomas into the PM subtype committed in early oligodendrocyte lineage. Here, we report the identification of EM/PM subtype-specific gene co-expression networks and the characterization of hub gene polypyrimidine tract-binding protein 1 (PTBP1) as a genomic alteration-independent vulnerability in IDH-wildtype GBM. Supervised by the EM/PM classification scheme, we applied weighted gene co-expression network analysis to identify subtype-specific global gene co-expression modules. These gene co-expression modules were characterized for their clinical relevance, cellular origin and conserved expression pattern during brain development. Using lentiviral vector-mediated constitutive or inducible knockdown, we characterized the effects of PTBP1 on the survival of IDH-wildtype GBM cells, which was complemented with the analysis of PTBP1-depedent splicing pattern and overexpression of splicing target neuron-specific CDC42 (CDC42-N) isoform.  Transcriptomes of adult gliomas can be robustly assigned into 4 large gene co-expression modules that are prognostically relevant and are derived from either malignant cells of the EM/PM subtypes or tumor microenvironment. The EM subtype is associated with a malignant cell-intrinsic gene module involved in pre-mRNA splicing, DNA replication and damage response, and chromosome segregation, and a microenvironment-derived gene module predominantly involved in extracellular matrix organization and infiltrating immune cells. The PM subtype is associated with two malignant cell-intrinsic gene modules predominantly involved in transcriptional regulation and mRNA translation, respectively. Expression levels of these gene modules are independent prognostic factors and malignant cell-intrinsic gene modules are conserved during brain development. Focusing on the EM subtype, we identified PTBP1 as the most significant hub for the malignant cell-intrinsic gene module. PTBP1 is not altered in most glioma genomes. PTBP1 represses the conserved splicing of CDC42-N. PTBP1 knockdown or CDC42-N overexpression disrupts actin cytoskeleton dynamics, causing accumulation of reactive oxygen species and cell apoptosis. PTBP1-mediated repression of CDC42-N splicing represents a potential genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype GBM.

MET fusions and splicing variants is a strong adverse prognostic factor in astrocytoma, isocitrate dehydrogenase mutant.

Liu et al. describe the adverse prognostic role of MET fusions and splicing variants in astrocytoma, isocitrate dehydrogenase mutant. On this basis, MET fusions and splicing variants was suggested to be a biomarker for the diagnosis of high-grade astrocytoma, isocitrate dehydrogenase mutant.

Poliovirus receptor-based chimeric antigen receptor T cells combined with NK-92 cells exert potent activity against glioblastoma.

BACKGROUND: Poliovirus receptor interacts with 3 receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif, CD96, and DNAX accessory molecule 1, which are predominantly expressed on T cells and natural killer (NK) cells. Many solid tumors, including IDH wild-type glioblastoma, have been reported to overexpress poliovirus receptor, and this overexpression is associated with poor prognosis. However, there are no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting poliovirus receptor in IDH wild-type glioblastoma. METHODS: We analyzed poliovirus receptor expression in transcriptome sequencing databases and specimens from IDH wild-type glioblastoma patients. We developed poliovirus receptor targeting chimeric antigen receptor T cells using lentivirus. The antitumor activity of chimeric antigen receptor T cells was demonstrated in patient-derived glioma stem cells, intracranial and subcutaneous mouse xenograft models. RESULTS: We verified poliovirus receptor expression in primary glioma stem cells, surgical specimens from IDH wild-type glioblastoma patients, and organoids. Accordingly, we developed poliovirus receptor-based second-generation chimeric antigen receptor T cells. The antitumor activity of chimeric antigen receptor T cells was demonstrated in glioma stem cells and xenograft models. Tumor recurrence occurred in intracranial xenograft models because of antigen loss. The combinational therapy of tyrosine-based inhibitory motif extracellular domain-based chimeric antigen receptor T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival. CONCLUSIONS: Poliovirus receptor-based chimeric antigen receptor T cells were capable of killing glioma stem cells and suppressing tumor recurrence when combined with NK-92 cells.

Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape.

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors. Although instances of rapid tumor remissions have been observed in animal models and clinical trials, tumor relapses occur with multiple therapeutic resistance mechanisms. Furthermore, while the mechanisms underlying the long-term therapeutic resistance are well-known, short-term adaptation remains less understood. However, more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance. In this study, we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells, a reversal of previously documented processes. This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction, also leading to short-term antigen loss and antigen masking. Such type of intercellular communication is independent of CAR downstream signaling, CAR-T cell condition, target antigen, and tumor cell type. However, it is mainly dependent on antigen density and CAR sensitivity, and is associated with tumor cell cholesterol metabolism. Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities. Together, our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma.

BACKGROUND: Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR-vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation. METHODS: Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo. RESULTS: GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models. CONCLUSIONS: Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

Diffuse Isocitrate Dehydrogenase-Mutant Gliomas With Histone H3 Alterations Are Distinguished by Unique Clinical Characteristics, Molecular Expression Profile, and Survival Prognosis.

BACKGROUND AND OBJECTIVES: Histopathological features and molecular biomarkers have been studied as potential prognostic factors. This study aimed to investigate the clinical features, molecular phenotypes, and survival prognosis of isocitrate dehydrogenase (IDH)-mutant (IDHmt) gliomas with histone H3 alterations (H3-alterations). METHODS: A total of 236 and 657 patients with whole-exome sequencing data were separately collected from the Chinese Glioma Genome Atlas and The Cancer Genome Atlas databases. Survival analysis of patients with glioma was performed using Kaplan-Meier survival curves stratified by histone H3 status. Univariate and multivariate analyses were used to identify the associations between histone H3 status and other clinicopathological factors with survival in patients with IDH-mutant gliomas. RESULTS: Diffuse gliomas with H3 alterations are more likely to be high grade in 2 cohorts ( P = .025 and P = .021, respectively). IDHmt glioma patients with H3-alteration had significantly less life expectancy than histone H3 wild-type ( P = .041 and P = .008, respectively). In the Chinese Glioma Genome Atlas cohort, Karnofsky performance scores ≤ 80 (HR 2.394, 95% CI 1.257-4.559, P = .008), extent of resection (HR 0.971, 95% CI 0.957-0.986, P < .001), high WHO grade (HR 6.938, 95% CI 2.787-17.269, P < .001), H3-alteration (HR 2.482, 95% CI 1.183-4.981, P = .016), and 1p/19q codeletion (HR 0.169, 95% CI 0.073-0.390, P < .001) were independently associated with IDHmt gliomas. In the The Cancer Genome Atlas cohort, age (HR 1.034, 95% CI 1.008-1.061, P = .010), high WHO grade (HR 2.365, 95% CI 1.263-4.427, P = .007), and H3-alteration (HR 2.501, 95% CI 1.312-4.766, P = .005) were independently associated with IDHmt gliomas. CONCLUSION: Identification and assessment of histone H3 status in clinical practice might help improve prognostic prediction and develop therapeutic strategies for these patient subgroups.

Stalled oligodendrocyte differentiation in IDH-mutant gliomas.

BACKGROUND: Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized. METHODS: Using bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers. RESULTS: Genes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas. CONCLUSIONS: Our studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas.

EGFRvIII Promotes the Proneural-Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis.

(1) Background: Glioblastoma multiforme (GBM) is the most common and malignant intracranial tumor in adults. At present, temozolomide (TMZ) is recognized as the preferred chemotherapeutic drug for GBM, but some patients have low sensitivity to TMZ or chemotherapy resistance to TMZ. Our previous study found that GBM patients with EGFRvIII (+) have low sensitivity to TMZ. However, the reasons and possible mechanisms of the chemoradiotherapy resistance in GBM patients with EGFRvIII (+) are not clear. (2) Methods: In this study, tissue samples of patients with GBM, GBM cell lines, glioma stem cell lines, and NSG mice were used to explore the causes and possible mechanisms of low sensitivity to TMZ in patients with EGFRvIII (+)-GBM. (3) Results: The study found that EGFRvIII promoted the proneural-mesenchymal transition of GBM and reduced its sensitivity to TMZ, and EGFRvIII regulated of the expression of ALDH1A3. (4) Conclusions: EGFRvIII activated the NF-κB pathway and further regulated the expression of ALDH1A3 to promote the proneural-mesenchymal transition of GBM and reduce its sensitivity to TMZ, which will provide an experimental basis for the selection of clinical drugs for GBM patients with EGFRvIII (+).

Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma.

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.

Immunological profiles of human oligodendrogliomas define two distinct molecular subtypes.

BACKGROUND: Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome. METHODS: 137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation. FINDINGS: We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts. INTERPRETATION: This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas. FUNDING: The funders are listed in the Acknowledgement.

Clinical characteristics and survival of glioblastoma complicated with non-central nervous system tumors.

BACKGROUND: Diagnosis and treatment of patients with glioblastoma (GBM) who are also diagnosed with primary non-central nervous system (CNS) tumors remain a challenge, yet little is known about the clinical characteristics and prognosis of these patients. The data presented here compared the clinical and pathological features between glioblastoma patients with or without primary non-CNS tumors, trying to further explore this complex situation. METHODS: Statistical analysis was based on the clinical and pathological data of 45 patients who were diagnosed with isocitrate dehydrogenase (IDH) wild-type glioblastoma accompanied by non-CNS tumors between January 2019 and February 2022 in Beijing Tiantan Hospital. Univariate COX proportional hazard regression model was used to determine risk factors for overall survival. RESULTS: It turned out to be no significant difference in the overall survival (OS) of the 45 patients with IDH-wild-type GBM plus non-CNS tumors, compared with the 112 patients who were only diagnosed with IDH-wild-type GBM. However, there was a significant difference in OS of GBM patients with benign tumors compared to those with malignant tumors. CONCLUSIONS: Implications for the non-central nervous system tumors on survival of glioblastomas were not found in this research. However, glioblastomas complicated with other malignant tumors still showed worse clinical outcomes.

WES data from 286 diffuse gliomas under the 2021 WHO Classification of Tumors of the Central Nervous System.

Diffuse gliomas (DGs) are the most common and lethal primary neoplasms in the central nervous system. The latest 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) was published in 2021, immensely changing the approach to diagnosis and decision making. As a part of the Chinese Glioma Genome Atlas (CGGA) project, our aim was to provide genomic profiling of gliomas in a Chinese cohort. Two hundred eighty six gliomas with different grades were collected over the last decade. Using the Illumina HiSeq platform, over 75.8 million high-quality 150 bp paired-end reads were generated per sample, yielding a total of 43.4 billion reads. We also collected each patient's clinical and pathological information and used it to annotate their genetic data. All patients were diagnosed and classified by neuro-pathologist under the 2021 WHO classification. This dataset provides an important reference for researchers and will significantly advance our understanding of gliomas.

Radiotherapy delays malignant transformation and prolongs survival in patients with IDH-mutant gliomas.

OBJECTIVE: IDH-mutant lower-grade gliomas (LGGs, grade 2 or 3) eventually transform into secondary grade 4 astrocytomas (sAIDHmut/G4). Here, we sought to describe the transformation time, risk factors, and outcomes in malignant transformation of IDH-mutant LGGs. METHODS: We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005-2021. We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4, and associated risk factors and outcomes. Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma. RESULTS: The median age of the 108 patients with IDH-mutant LGGs was 35 years (range, 19-54); the median age at transformation was 40 years (range, 25-62); and the median follow-up time for all patients was 146 months (range, 121-171). The average transformation time was 58.8 months for all patients with LGGs (range, 5.9-208.1); 63.5 and 51.9 months for grade 2 and 3 gliomas, respectively; and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas, respectively. Univariate and multivariate analysis indicated that radiotherapy [hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.137-0.595; P = 0.001] and non-A blood type (HR, 0.37; 95% CI, 0.203-0.680; P = 0.001) were protective factors against delayed malignant transformation. Radiotherapy was associated with improved survival after transformation (HR, 0.44; 95% CI, 0.241-0.803; P = 0.008), overall survival (HR, 0.50; 95% CI, 0.265-0.972; P = 0.041), and progression-free survival (HR, 0.25; 95% CI, 0.133-0.479; P < 0.0001) in patients with IDH-mutant gliomas. CONCLUSIONS: Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDH-mutant gliomas.

Clinical management and survival outcomes of patients with different molecular subtypes of diffuse gliomas in China (2011-2017): a multicenter retrospective study from CGGA.

OBJECTIVE: We aimed to summarize the clinicopathological characteristics and prognostic features of various molecular subtypes of diffuse gliomas (DGs) in the Chinese population. METHODS: In total, 1,418 patients diagnosed with DG between 2011 and 2017 were classified into 5 molecular subtypes according to the 2016 WHO classification of central nervous system tumors. The IDH mutation status was determined by immunohistochemistry and/or DNA sequencing, and 1p/19q codeletion was detected with fluorescence in situ hybridization. The median clinical follow-up time was 1,076 days. T-tests and chi-square tests were used to compare clinicopathological characteristics. Kaplan-Meier and Cox regression methods were used to evaluate prognostic factors. RESULTS: Our cohort included 15.5% lower-grade gliomas, IDH-mutant and 1p/19q-codeleted (LGG-IDHm-1p/19q); 18.1% lower-grade gliomas, IDH-mutant (LGG-IDHm); 13.1% lower-grade gliomas, IDH-wildtype (LGG-IDHwt); 36.1% glioblastoma, IDH-wildtype (GBM-IDHwt); and 17.2% glioblastoma, IDH-mutant (GBM-IDHm). Approximately 63.3% of the enrolled primary gliomas, and the median overall survival times for LGG-IDHm, LGG-IDHwt, GBM-IDHwt, and GBM-IDHm subtypes were 75.97, 34.47, 11.57, and 15.17 months, respectively. The 5-year survival rate of LGG-IDHm-1p/19q was 76.54%. We observed a significant association between high resection rate and favorable survival outcomes across all subtypes of primary tumors. We also observed a significant role of chemotherapy in prolonging overall survival for GBM-IDHwt and GBM-IDHm, and in prolonging post-relapse survival for the 2 recurrent GBM subtypes. CONCLUSIONS: By controlling for molecular subtypes, we found that resection rate and chemotherapy were 2 prognostic factors associated with survival outcomes in a Chinese cohort with DG.

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

BACKGROUND: mRNA 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. METHODS: In 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. RESULTS: PTBP1 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. CONCLUSION: In 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.

Corrigendum: Comprehensive analysis of the clinical and biological significances of endoplasmic reticulum stress in diffuse gliomas.

[This corrects the article DOI: 10.3389/fcell.2021.619396.].

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

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.