Overexpression of oncostatin M receptor regulates local immune response in glioblastoma.

Glioblastoma (GBM) is the most lethal cancer in central nervous system. It is urgently needed to look for novel therapeutics for GBM. Oncostatin M receptor (OSMR) is a cytokine receptor gene of IL-6 family and has been reported to be involved in regulating GBM tumorigenesis. However, the role of OSMR regulating the disrupted immune response in GBM need to be further investigated. Three gene expression profiles, Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) data set (GSE16011), were enrolled in our study and used for OSMR expression and survival analysis. The expression of OSMR was further verified with immunohistochemistry and western blot analysis in glioma tissues. Microenvironment cell populations-counter (MCP-counter) was applied for analyzing the relationship between OSMR expression and nontumor cells. The functions of OSMR in GBM was investigated by Gene Ontology, Gene set enrichment analysis (GSEA), gene set variation analysis and so on. The analysis of cytokine receptor activity-related genes in glioma identifies OSMR as a gene with an independent predictive factor for progressive malignancy in GBM. Furthermore, OSMR expression is a prognostic marker in the response prediction to radiotherapy and chemotherapy. OSMR contributes to the regulation of local immune response and extracellular matrix process in GBM. Our findings define an important role of OSMR in the regulation of local immune response in GBM, which may suggest OSMR as a possible biomarker in developing new therapeutic immune strategies in GBM.

Gremlin1 promotes carcinogenesis of glioma in vitro.

As the most prevalent and lethal type of brain tumours, gliomas, especially malignant ones, are relatively resistant to conventional therapies. Gremlin 1 (GREM1) is a secreted glycoprotein that is implicated in the maintenance of cancer stem cells in tumour hierarchy. In the current study, the role of GREM1 in the carcinogenesis of glioma was studied using a knockdown approach. We first examined the expression level of GREM1 in the clinical samples, and then evaluated the effect of GREM1 knockdown on the viability and colony formation capacity of U87-MG cells. Moreover, the migration ability, invasiveness, cell cycle, and apoptosis of GREM1-silenced cells were assessed. Furthermore, the involvement of functional GREM1 in the epithelial-mesenchymal transition (EMT) process of glioma was investigated by detecting the expression levels of glioma-associated oncogene homologue 3 (GLI3) and EMT-related molecules. Our results demonstrated that knockdown of GREM1 reduced cell viability, suppressed migration and invasion, and inhibited GLI3 expression and the EMT process in U87-MG cells. Meanwhile, GREM1 silencing promoted apoptosis in U87-MG cells through the accumulation of Bax, cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP) as well as the downregulation of Bcl-2. In addition, GREM1 knockdown abolished transforming growth factor (TGF)-ß1-mediated activation of the Smad pathway, which may underlie the mechanism of GREM1-regulated EMT. In conclusion, GREM1 plays an important role in the development of glioma, and it may serve as a potential target in glioma therapy.

Inhibiting interferon-γ induced cancer intrinsic TNFRSF14 elevation restrains the malignant progression of glioblastoma.

BACKGROUND: Prolonged interferon-γ signaling activation induces cancer resistance to therapeutics, especially immunotherapy. However, the detailed mechanisms are not well characterized. In present study, we explored cancer intrinsic resistant mechanisms employing for evading immune checkpoint blockade (ICB) and searched for key immune checkpoints contributing to the constitution of suppressive immune microenvironment of glioblastoma (GBM). METHODS: We screened key immune checkpoint (IC) associated with IFN signaling activation in GBM according to integrated transcriptomic profiling on the ICs. Expression analysis and functional assays revealed that malignant cells elevated the key IC, TNFRSF14 expression under IFN-γ stimulation, which enhanced their proliferation and in vivo tumorigenicity. Therapeutic efficiency of TNFRSF14 disruption in GBM was evaluated with in vitro and in vivo functional assays, including immunofluorescence, transwell, RT-qPCR, flow cytometry, mass cytometry, and mice preclinical GBM models. Moreover, the improvement of TNFRSF14 blockade on the efficacy of PD-L1 treatment was examined in mice intracranial xenograft bearing models. RESULTS: TNFRSF14, a previously poorly characterized IC, was disclosed as a checkpoint with malignant intrinsic elevation closely associated with type II not type I IFN signaling activation in GBM. Anti-PD-L1 treatment induces compensatory TNFRSF14 elevation, while enhancing IFN-γ production. TNFRSF14 phosphorylates FAK at Y397 and consequently activates NF-κB, which not only strengthens the tumorigenicity of GBM cells, but also enhances TAMs recruitment through elevating CXCL1/CXCL5 secretion from GBM cells. TNFRSF14 ablation reduces the tumorigenicity of GBM cells, reshapes the immunosuppressive microenvironment, and enhances therapeutic efficacy of anti-PD-L1 in mouse orthotopic GBM model. CONCLUSION: Our findings highlight a malignant TNFRSF14/FAK axis as a potential target to blunt cancer-intrinsic resistance to ICB treatment, which may help improve the therapeutic efficiency of immunotherapy in malignancies.

Primary central nervous system diffuse large B-cell lymphoma in fourth ventricle: Case report and literature review.

RATIONALE: Primary central nervous system lymphoma (PCNSL) is rare, especially lymphoma arising in the fourth ventricle. Only a few cases have been reported. We report a case of fourth ventricular lymphoma and review the relevant literature. Characterizing these cases can provide a basis for optimizing the diagnosis and management of fourth ventricle lymphoma. PATIENT CONCERNS: A 48-year-old male with blurred vision, dizziness, staggering persisting for 2 months was admitted. DIAGNOSIS: Preoperative magnetic resonance imaging revealed a space occupying lesion of the fourth ventricle. The patient presented with symptoms of hydrocephalus before surgery, such as memory loss and slurred speech. Pathological analysis following complete resection confirmed the lesion as PCNSL. INTERVENTION: The patient underwent a midline posterior fossa craniotomy. OUTCOMES: The patient symptoms were relieved after surgery. Postoperative chemotherapy was administered with our regular follow-up. Follow-up 9 months after operation indicated a good prognosis. LESSONS: According to the literature, biopsy surgery and subsequent chemotherapy are generally considered as the best treatment options for PCNSL. We believe that for the special location of the fourth ventricle, lymphomas in this site are suitable for the combination of complete resection and subsequent chemotherapy. This approach facilitates tumor resection and reduces possibility of obstructive hydrocephalus.

Risk factors of cerebrospinal fluid leakage after neuroendoscopic transsphenoidal pituitary adenoma resection: a systematic review and meta-analysis.

Introduction: Cerebro spinal fluid (CSF) leakage is common and might lead to severe postoperative complications after endoscopic transsphenoidal pituitary adenoma resection. However, the risk factors of postoperative CSF leakage are still controversial. This article presents a systematic review to explore the explicit risk factors of CSF leakage after endoscopic transsphenoidal pituitary adenomere section. Methods: PRISMA and AMSTAR guidelines were followed to assess the methodological quality of the systematic review. PubMed, Medline, Embase, Web of Science, Cochrane, Clinical Trails, CNKI, CBM, Wan Fang, and VIP databases were searched for all studies on postoperative CSF leak risk factors. The quality of the included studies was assessed by the Newcastle-Ottawa scale. Review Manager 5.4 software was used to calculate the pooled effect size of potential factors with statistical significance. Results: A total of 6775 patients with pituitary adenoma across 18 articles were included, containing 482 cases of postoperative CSF leakage (accounting for 7.11%). All of the articles had a quality score > 5, indicating good quality. Meta-analysis showed that an increased risk of CSF leak was found for higher levels of BMI (MD=1.91, 95% CI (0.86,2.96), bigger tumor size [OR=4.93, 95% CI (1.41,17.26)], greater tumor invasion (OR=3.01, 95% CI (1.71, 5.31), the harder texture of tumor [OR=2.65, 95% CI (1.95,3.62)], intraoperative cerebrospinal fluid leakage [OR=5.61, 95% CI (3.53,8.90)], multiple operations [OR=2.27, 95% CI (1.60,3.23)]. Conclusion: BMI, multiple operations, tumor size, tumor invasion, hard texture, and intraoperative cerebrospinal fluid leakage are the risk factors of postoperative CSF leakage. Clinical doctors should pay attention to these risk factors, and conduct strict skull base reconstruction and careful postoperative management.

Tumor microenvironment remodeling plus immunotherapy could be used in mesenchymal-like tumor with high tumor residual and drug resistant rate.

Epithelial-mesenchymal transition (EMT) is a common process during tumor progression and is always related to residual tumor, drug resistance and immune suppression. However, considering the heterogeneity in EMT process, there is still a need to establish robust EMT classification system with reasonable molecular, biological and clinical implications to investigate whether these unfavorable survival factors are common or unique in different individuals. In our work, we classify tumors with four EMT status, that is, EMTlow, EMTmid, EMThigh-NOS (Not Otherwise Specified), and EMThigh-AKT (AKT pathway overactivation) subtypes. We find that EMThigh-NOS subtype is driven by intrinsic somatic alterations. While, EMThigh-AKT subtype is maintained by extrinsic cellular interplay between tumor cells and macrophages in an AKT-dependent manner. EMThigh-AKT subtype is both unresectable and drug resistant while EMThigh-NOS subtype can be treated with cell cycle related drugs. Importantly, AKT activation in EMThigh-AKT not only enhances EMT process, but also contributes to the immunosuppressive microenvironment. By remodeling tumor immune-microenvironment by AKT inhibition, EMThigh-AKT can be treated by immune checkpoint blockade therapies. Meanwhile, we develop TumorMT website ( http://tumormt.neuroscience.org.cn/ ) to apply this EMT classification and provide reasonable therapeutic guidance.

Dual role of ARPC1B in regulating the network between tumor-associated macrophages and tumor cells in glioblastoma.

The tumor microenvironment (TME) plays a critical role in promoting the growth and metastasis of glioblastoma (GBM). Tumor-associated macrophages (TAMs), the most abundant myeloid cells infiltrating in TME, produce proinflammatory cytokines, regulate glioma cell pools, and lead to GBM progression. Understanding the mechanism of GBM-TAMs regulation can help to find new targeted therapeutic strategies against GBM. Based on the CGGA and TCGA GBM cohorts, ARPC1B was defined as the key macrophage-associated gene with prognostic value. Higher ARPC1B expression was associated with progressive malignancy, poor outcomes and TAM infiltration. We demonstrated that macrophage-expressed ARPC1B promoted the migration, invasion, and epithelial-mesenchymal transition of glioma cells. Glioma-intrinsic ARPC1B also maintained the malignant phenotype and promoted macrophage recruitment. Positive feedback signaling between macrophages and glioma cells via ARPC1B was determined to be under control of the IFNγ-IRF2-ARPC1B axis. This study highlights the important role of ARPC1B in GBM malignancy progression and the regulation network between GBM and TAMs, suggesting ARPC1B as a novel biomarker with potential therapeutic implications.

Cancer cell intrinsic TIM-3 induces glioblastoma progression.

Glioblastoma (GBM) is identified to share common signal pathways between glioma and immune cells. Here, we find that T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) is one of the most common co-inhibitory immune checkpoints in GBM shared by tumor and non-tumor cells. Glioma cell-intrinsic TIM-3 is involved in not only regulating malignant behaviors of glioma cells but also inducing macrophage migration and transition to anti-inflammatory/pro-tumorigenic phenotype by a TIM-3/interleukin 6 (IL6) signal. In mechanism, as one of the major regulators of IL6, TIM-3 regulates its expression through activating NF-κB. Blocking this feedback loop by Tocilizumab, an IL6R inhibitor, inhibited the above effects and repressed the tumorigenicity of GBM in vivo. Our work identifies glioma cell-intrinsic functions of TIM-3/IL6 signal mediating the crosstalk feedback loop between glioma cells and tumor-associated macrophages (TAMs). Blocking this feedback loop may provide a novel therapeutic strategy for GBM.

Molecular profiling identifies distinct subtypes across TP53 mutant tumors.

Tumor protein 53 mutation (TP53mut) is one of the most important driver events facilitating tumorigenesis, which could induce a series of chain reactions to promote tumor malignant transformation. However, the malignancy progression patterns under TP53 mutation remain less known. Clarifying the molecular landscapes of TP53mut tumors will help us understand the process of tumor development and aid precise treatment. Here, we distilled genetic and epigenetic features altered in TP53mut cancers for cluster-of-clusters analysis. Using integrated classification, we derived 5 different subtypes of TP53mut patients. These subtypes have distinct features in genomic alteration, clinical relevance, microenvironment dysregulation, and potential therapeutics. Among the 5 subtypes, COCA3 was identified as the subtype with worst prognosis, causing an immunosuppressive microenvironment and immunotherapeutic resistance. Further drug efficacy research highlighted olaparib as the most promising therapeutic agents for COCA3 tumors. Importantly, the therapeutic efficacy of olaparib in COCA3 and immunotherapy in non-COCA3 tumors was validated via in vivo experimentation. Our study explored the important molecular events and developed a subtype classification system with distinct targeted therapy strategies for different subtypes of TP53mut tumors. These multiomics classification systems provide a valuable resource that significantly expands the knowledge of TP53mut tumors and may eventually benefit in clinical practice.

Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance.

BACKGROUND: Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment, and immunotherapy is still poorly understood. METHODS: Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components, and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma. RESULTS: Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes, and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand-1 (PD-L1) blockade generated a synergistic therapeutic outcome in GBM murine models. CONCLUSIONS: This work provides a molecular, clinical, and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade treatment with ferroptosis inhibition.

Genome profiling of mismatch repair genes in eight types of tumors.

Mismatch repair (MMR) plays an important role in the occurrence and development of tumors. At present, it is widely believed that MMR is a protective mechanism of tumors that plays a critical role in the progresses of cancer. In this study, 34 genes related to MMR selected from Gene Ontology (GO) database were scored by single sample Gene sets enrichment analysis (ssGSEA), and eight cancers were screened from 23 TCGA solid cancers to investigate the clinical significance of MMR score. MMR had different effects on the prognosis of the eight tumors, with a protective effect in three cancers and functioning as a risk factor in the remaining five cancers. We used unsupervised clustering to divide the patients into four clusters. We found that the immune and metabolic status of the four clusters were extremely different, among which cluster1 had the lowest tumor purity and the most complex microenvironment; this may explain its poor prognosis and immunotherapy effect. In summary, MMR scores can improve the predictive ability and provide effective guidance for immunotherapy in individual type of tumors.

The Systematic Landscape of Nectin Family and Nectin-Like Molecules: Functions and Prognostic Value in Low Grade Glioma.

Objective: Nectin and nectin-like molecules (Necls) are molecules that are involved in cell-cell adhesion and other vital cellular processes. This study aimed to determine the expression and prognostic value of nectin and Necls in low grade glioma (LGG). Materials and Methods: Differentially expressed nectin and Necls in LGG samples and the relationship of nectin family and Necls expression with prognosis, clinicopathological parameters, and survival were explored using The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and Repository of Molecular Brain Neoplasia Data (REMBRANDT) databases. Univariate and multivariate Cox analysis models were performed to construct the prognosis-related gene signature. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves and multivariate Cox regression analysis, were utilized to evaluate the prognostic capacity of the four-gene signature. Gene ontology (GO)enrichment analysis and Gene Set Enrichment Analyses (GSEA) were performed to further understand the underlying molecular mechanisms. The Tumor Immune Estimation Resource (TIMER) was used to explore the relationship between the four-gene signature and tumor immune infiltration. Results: Several nectin and Necls were differentially expressed in LGG. Kaplan-Meier survival analyses and Univariate Cox regression showed patients with high expression of NECTIN2 and PVR and low expression of CADM2 and NECTIN1 had worse prognosis among TCGA, CGGA, and REMBRANDT database. Then, a novel four-gene signature was built for LGG prognosis prediction. ROC curves, KM survival analyses, and multivariate COX regression indicated the new signature was an independent prognostic indicator for overall survival. Finally, GSEA and GO enrichment analyses revealed that immune-related pathways participate in the molecular mechanisms. The risk score had a strong negative correlation with tumor purity and data of TIMER showed different immune cell proportions (macrophage and myeloid dendritic cell) between high- and low-risk groups. Additionally, signature scores were positively related to multiple immune-related biomarkers (IL 2, IL8 and IFNγ). Conclusion: Our results offer an extensive analysis of nectin and Necls levels and a four-gene model for prognostic prediction in LGG, providing insights for further investigation of CADM2, NECTIN1/2, and PVR as potential clinical and immune targets in LGG.

IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma.

PURPOSE: As a crucial part of anti-tumor immunotherapy, interferon-α/ß (IFN-α/ß) treatment has been broadly applied to clinical trials of glioma. However, less is known about implement of interferon-γ (IFN-γ) in glioma. Further investigating the valuable hub molecular of IFN-γ family might provide us a novel guidance for glioma therapy. METHODS: This study carried out an analysis on glioma patients from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts. The analyses were performed by GraphPad Prism 8 and R language. All the validated experiments were performed three times independently. RESULTS: We identified IFI30 as the most stable independent prognostic gene among 20 classical IFN-γ stimulated genes (ISGs) in glioma patients. Furthermore, we found that IFI30 highly expressed in malignant subtypes of glioma and associated with chemotherapy response. We also found IFI30 could activate IL6-STAT6 signal pathway to decline the glioma cells' chemotherapy sensitivity by performing experiments. Gene ontology (GO) analysis showed IFI30 associated with enhanced leucocyte mediated immune and inflammatory response. Microenvironment analysis referred that high IFI30 expression accompanied with more infiltration of M2 type macrophages. CONCLUSION: IFI30 is involved in the malignant progression and chemotherapy response of glioblastoma, which can be a potential target for treatment in glioblastoma patients.

Characterization of ROS Metabolic Equilibrium Reclassifies Pan-Cancer Samples and Guides Pathway Targeting Therapy.

Background: Abnormal redox equilibrium is a major contributor to tumor malignancy and treatment resistance. Understanding reactive oxygen species (ROS) metabolism is a key to clarify the tumor redox status. However, we have limited methods to evaluate ROS in tumor tissues and little knowledge on ROS metabolism across human cancers. Methods: The Cancer Genome Atlas multi-omics data across 22 cancer types and the Genomics of Drug Sensitivity in Cancer data were analyzed in this study. Cell viability testing and xenograft model were used to validate the role of ROS modulation in regulating treatment efficacy. Results: ROS indexes reflecting ROS metabolic balance in five dimensions were developed and verified. Based on the ROS indexes, we conducted ROS metabolic landscape across 22 cancer types and found that ROS metabolism played various roles in different cancer types. Tumor samples were classified into eight ROS clusters with distinct clinical and multi-omics features, which was independent of their histological origin. We established a ROS-based drug efficacy evaluation network and experimentally validated the predicted effects, suggesting that modulating ROS metabolism improves treatment sensitivity and expands drug application scopes. Conclusion: Our study proposes a new method in evaluating ROS status and offers comprehensive understanding on ROS metabolic equilibrium in human cancers, which provide practical implications for clinical management.

Elevated lymphocyte specific protein 1 expression is involved in the regulation of leukocyte migration and immunosuppressive microenvironment in glioblastoma.

Immune cell infiltration mediates therapeutic response to immune therapies. The investigation on the genes regulating leukocyte migration may help us to understand the mechanisms regulating immune cell infiltration in tumor microenvironment. Here, we collected the data from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) to analyze the expression of leukocyte migration related genes in glioblastoma (GBM). Lymphocyte specific protein 1 (LSP1) was identified as the only gene in this family which not only has an elevated expression, but also serve as an independent predictive factor for progressive malignancy in glioma. We further confirmed these results in clinical glioma samples by quantitative PCR, immunofluorescence, immunohistochemistry, and western blot. Moreover, LSP1 expression was closely related to the response to radio- and chemotherapy in GBM, and positively correlated with immunosuppressive cell populations, including M2 macrophages, neutrophil, and regulatory T cell. Additionally, elevated LSP-1 expression enhanced the expression of immunosuppression related genes like programmed cell death 1 (PD1) and leukocyte associated immunoglobulin like receptor 1 (LAIR1) in macrophages. LSP1 also promoted the migration of macrophages. Together, our study suggests a novel role of LSP1 contributing to immunosuppressive microenvironment in GBM and serving as a potential therapeutic target for it.

Costimulatory checkpoint SLAMF8 is an independent prognosis factor in glioma.

AIMS: Immune checkpoint blockade has made breakthroughs in immunotherapy for glioma. However, current immunotherapy has therapeutic benefits only in a subset of patients and accompanied by immune-related side effects. SLAMF8 is a costimulatory molecule that affects the activation of macrophages in inflammation. The study of SLAMF8 may provide new information for immunological research and treatment of glioma. METHODS: CGGA and TCGA cohorts of 946 patients with RNA sequencing data and full clinical information were analyzed using R language and GraphPad Prism 7. RESULTS: SLAMF8 was overexpressed along with malignancy progression and was a biomarker of mesenchymal subtype. As an independent prognostic factor, high SLAMF8 conferred reduced overall survival and chemotherapy resistance. SLAMF8 implied lower proportion of cancer cells along with increasing enrichment of monocytic lineage, myeloid dendritic cells. Functional analysis showed higher SLAMF8 indicated activation of antigen processing and presenting and the IFN-γ/TNF/TLR-mediated signaling. Meanwhile, coexpressing with classical checkpoint SLAMF8 aggravated immunosuppression and enhanced inflammation response. CONCLUSION: Our study highlighted the important role of SLAMF8 in malignancy progression, shortened survival, and immune disorders. Further research on SLAMF8 in immunosuppression and inflammation response to glioma cells could aid immunotherapy for glioma.

Integrated profiling identifies caveolae-associated protein 1 as a prognostic biomarker of malignancy in glioblastoma patients.

AIMS: Glioblastoma (GBM) is a lethal disease of the central nervous system with high mortality, and novel therapeutic targets and strategies for GBM are urgently needed. Caveolae-associated protein 1 (CAVIN1) is an essential caveolar component-encoding gene and has been poorly studied in glioma. To this end, in this study, we evaluated CAVIN1 expression in glioma tissue as well as the correlation between CAVIN1 expression and prognosis in glioma patients using the data collected from clinical samples or from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Rembrandt, and Gene Expression Omnibus (GEO) data sets. METHODS: Survival analysis was performed with the Kaplan-Meier curve and log-rank test. The predictive role of CAVIN1 in progressive malignancy in glioma was evaluated by using a receiver operator characteristic (ROC) curve. Gene ontology (GO), Gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) methods were used to interpret the functions of CAVIN1 in GBM. RESULTS: CAVIN1 expression was elevated in GBM compared with that in low-grade glioma and nontumor brain samples and was correlated with unfavorable outcomes in glioma patients. Additionally, CAVIN1 could serve as an independent predictive factor for progressive malignancy in GBM. Furthermore, CAVIN1 was associated with disrupted angiogenesis and immune response in the tumor microenvironment of GBM. CONCLUSIONS: We identified CAVIN1 as a prognostic biomarker and potential target for developing novel therapeutic strategies against GBM.

CD48 is a key molecule of immunomodulation affecting prognosis in glioma.

Purpose: Glioma is a refractory disease associated with immune cell infiltration, and the effectiveness of checkpoint blockade remains suboptimal. As an adhesion and costimulatory molecule, CD48 plays a significant role in immunomodulation. As such, studying CD48 may provide additional understanding of the immune and inflammation response of glioma. Methods: Using R language and GraphPad Prism 7, RNA sequencing data of 946 patients from Chinese Glioma Genome Atlas and The Cancer Genome Atlas cohorts were analyzed. Results: CD48 was highly expressed in the malignant progression of glioma. As an independent risk factor, high-CD48 patients were associated with poor prognosis. CD48 influenced glioma purity and the local immune cell subpopulation. CD48 was closely related to immune function in glioma. Patients with an enhanced immune phenotype, high CD48, were associated with immune suppressive molecules and checkpoints. In addition, CD48 correlated with the immune and inflammatory response. A checkpoint risk score including CD48, SLAMF8 and PD-L1 was used to assess the role of checkpoints. Risk score was particularly high in a malignant subtype of glioma and was an independent predictive indicator of unfavorable outcome. Additionally, age, IDH subtype and MGMT promoter status influenced the predictive significance of checkpoint risk score. Conclusion: CD48 exhibits a crucial role in reduced survival and immunomodulation in glioma. In addition, we found that checkpoints play a greater role in patients older than 40 years old with IDH wild-type and MGMT methylated status. These findings suggest that combining CD48 blockade with PD-L1 may be a promising approach to glioma immunotherapy for specific subpopulations of patients.

Development and validation of an interferon signature predicting prognosis and treatment response for glioblastoma.

Background: Interferon treatment, as an important approach of anti-tumor immunotherapy, has been implemented in multiple clinical trials of glioma. However, only a small number of gliomas benefit from it. Therefore, it is necessary to investigate the clinical role of interferons and to establish robust biomarkers to facilitate its application. Materials and methods: This study reviewed 1,241 glioblastoma (GBM) and 1,068 lower grade glioma (LGG) patients from six glioma cohorts. The transcription matrix and clinical information were analyzed using R software, GraphPad Prism 7 and Medcalc, etc. Immunohistochemical (IHC) staining were performed for validation in protein level. Results: Interferon signaling was significantly enhanced in GBM. An interferon signature was developed based on five interferon genes with prognostic significance, which could reflect various interferon statuses. Survival analysis showed the signature could serve as an unfavorable prognostic factor independently. We also established a nomogram model integrating the risk signature into traditional prognostic factors, which increased the validity of survival prediction. Moreover, high-risk group conferred resistance to chemotherapy and high IFNB1 expression levels. Functional analysis showed that the high-risk group was associated with overloaded immune response. Microenvironment analysis and IHC staining found that high-risk group occupied a disorganized microenvironment which was characterized by an enrichment of M0 macrophages and neutrophils, but less infiltration of activated nature killing (NK) cells and M1 type macrophages. Conclusion: This interferon signature was an independent indicator for unfavorable prognosis and showed great potential for screening out patients who will benefit from chemotherapy and interferon treatment.

Primary Extradural Melanoma Arising in Cervical Spinal Nerve Root.

BACKGROUND: Primary cervical melanoma is rare; this is especially true of extradural melanoma arising in the nerve root. Characterizing these cases can provide a basis for improved melanoma management. CASE DESCRIPTION: A 42-year-old female patient with numbness and pain in the right shoulder and arm persisting for 5 years was admitted. Preoperative magnetic resonance imaging revealed an epidural ladle-shaped mass shape beyond the C7-T1 intervertebral foramen that resembled a nerve sheath tumor. Histopathologic analysis following complete resection confirmed the lesion as malignant melanoma. Radiotherapy and temozolomide and cisplatin chemotherapy were administered in an accompanying hospital with regular follow-ups at our institution. After 2 months of postoperative adjuvant therapy, hepatic metastatic lesions developed. The chemotherapy regimen was changed to carboplatin, nab-paclitaxel, and recombinant human endostatin injections for a 6-month period. Follow-up 8 months after chemotherapy (16 months post surgery) indicated a good prognosis. CONCLUSIONS: In the past 10 years only 1 case of primary extradural spinal melanoma in cervical intervertebral foramen has been described, with no reported cases of hepatic metastasis. As radiographic results are not unequivocal, a diagnosis of spinal melanoma must be based on postoperative histologic confirmation. However, to date there is no standard postoperative adjuvant therapy for these patients. The chemotherapy regimen described in this report has broader implications for melanoma treatment.