Glioma Tumor Microenvironment Research Articles

The role of APOBEC3C in modulating the tumor microenvironment and stemness properties of glioma: evidence from pancancer analysis.

It is now understood that APOBEC3 family proteins (A3s) are essential in tumor progression, yet their involvement in tumor immunity and stemness across diverse cancer types remains poorly understood. In the present study, comprehensive genome-wide statistical and bioinformatic analyses were conducted to elucidate A3 family expression patterns, establishing clinically relevant correlations with prognosis, the tumor microenvironment(TME), immune infiltration, checkpoint blockade, and stemness across cancers. Different experimental techniques were applied, including RT-qPCR, immunohistochemistry, sphere formation assays, Transwell migration assays, and wound-healing assays, to investigate the impact of A3C on low-grade glioma (LGG) and glioblastoma multiforme (GBM), as well as its function in glioma stem cells(GSCs). Dysregulated expression of A3s was observed in various human cancer tissues. The prognostic value of A3 expression differed across cancer types, with a link to particularly unfavorable outcomes in gliomas. A3s are associated with the the TME and stemness in multiple cancers. Additionally, we developed an independent prognostic model based on A3s expression, which may be an independent prognostic factor for OS in patients with glioma. Subsequent validation underscored a strong association between elevated A3C expression and adverse prognostic outcomes, higher tumor grades, and unfavorable histology in glioma. A potential connection between A3C and glioma progression was established. Notably, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses implicated A3C in immune system-related diseases, with heightened A3C levels contributing to an immunosuppressive tumor microenvironment (TME) in glioma. Furthermore, in vitro experiments substantiated the role of A3C in sustaining and renewing glioma stem cells, as A3C deletion led to diminished proliferation, invasion, and migration of glioma cells. The A3 family exhibits heterogeneous expression across various cancer types, with its expression profile serving as a predictive marker for overall survival in glioma patients. A3C emerges as a regulator of glioma progression, exerting its influence through modulation of the tumor microenvironment and regulation of stemness.

Ceruloplasmin is associated with the infiltration of immune cells and acts as a prognostic biomarker in patients suffering from glioma.

Glioma is regarded as a prevalent form of cancer that affects the Central Nervous System (CNS), with an aggressive growth pattern and a low clinical cure rate. Despite the advancement of the treatment strategy of surgical resection, chemoradiotherapy and immunotherapy in the last decade, the clinical outcome is still grim, which is ascribed to the low immunogenicity and tumor microenvironment (TME) of glioma. The multifunctional molecule, called ceruloplasmin (CP) is involved in iron metabolism. Its expression pattern, prognostic significance, and association with the immune cells in gliomas have not been thoroughly investigated. Studies using a variety of databases, including Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gliovis, showed that the mRNA and protein expression levels of CP in patients suffering from glioma increased significantly with an increasing glioma grade. Kaplan-Meier (KM) curves and statistical tests highlighted a significant reduction in survival time of patients with elevated CP expression levels. According to Cox regression analysis, CP can be utilized as a stand-alone predictive biomarker in patients suffering from glioma. A significant association between CP expression and numerous immune-related pathways was found after analyzing the data using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Tumor Immune Estimation Resource (TIMER) and CIBERSORT analyses indicated a substantial correlation between the CP expression and infiltration of immunocytes in the TME. Additionally, immune checkpoints and CP expression in gliomas showed a favorable correlation. According to these results, patients with glioma have better prognoses and levels of tumor immune cell infiltration when their CP expression is low. As a result, CP could be used as a probable therapeutic target for gliomas and potentially anticipate the effectiveness of immunotherapy.

Genetically modified IL2 bone-marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment

Gliomas are one of the leading causes of cancer-related death in the adolescent and young adult (AYA) population. Two-thirds of AYA glioma patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Malignant progression is supported by the immunosuppressive stromal component of the tumor microenvironment (TME) exacerbated by M2 macrophages and a paucity of cytotoxic Tcells. A single intravenous dose of engineered bone-marrow-derived myeloid cells that release interleukin-2 (GEMys-IL2) was used to treat mice with LGGs. Our results demonstrate that GEMys-IL2 crossed the blood-brain barrier, infiltrated the TME, and reprogrammed the immune cell composition and transcriptome. Moreover, GEMys-IL2 extended survival in an LGG immunocompetent mouse model. Here, we report the efficacy of an invivo approach that demonstrates the potential for a cell-mediated innate immunotherapy designed to enhance the recruitment of activated effector T and natural killer cells within the glioma TME.

Development and validation of cuproptosis molecular subtype-related signature for predicting immune prognostic characterization in gliomas.

Cuproptosis, a novel programmed cell death, plays an important role in glioma growth, angiogenesis, and immune response. Nonetheless, the role of cuproptosis-related genes (CRGs) in the prognosis and tumor microenvironment (TME) of gliomas remains unknown. By non-negative matrix factorization consensus clustering, 1286 glioma patients were classified based on the mRNA expression levels of 27 CRGs and investigated the association of immune infiltration and clinical characteristics with cuproptosis subtypes. A CRG-score system was constructed using LASSO and multivariate Cox regression methods and validated in independent cohorts to predict the prognosis of glioma patients. Glioma patients were divided into two cuproptosis subtypes. Cluster C2 was enriched in immune-related pathways, had higher macrophage M2, neutrophils, and CD8 + T cells, and poorer prognosis compared with cluster C1 which was enriched in metabolism-related pathways. We further constructed and validated the ten-gene CRG risk scores. Glioma patients in the high CRG-score group had higher tumor mutation burden, higher TME scores, and poorer prognoses compared with the low CRG-score group. Additionally, the AUC value of the CRG-score was 0.778 in predicting the prognosis of gliomas. WHO grading, IDH mutation, 1p/19q codeletion, and MGMT methylation were significant differences between high and low CRG-score groups. This study demonstrated that CRG-score was related to immune cell infiltration and could accurately predict gliomas' prognosis. Our findings may provide a novel understanding of the potential role of cuproptosis molecular pattern and TME in the immune response and prognosis of glioma patients.

Deciphering glioma epitranscriptome: focus on RNA modifications.

Gliomas are highly malignant tumors accounting for the majority of brain neoplasms. They are characterized by nuclear atypia, high mitotic rate and cellular polymorphism that often contributes to aggressiveness and resistance to standard therapy. They often associate with challenging treatment approaches and poor outcomes. New treatment strategies or regimens to improve the efficacy of glioma treatment require a deeper understanding of glioma occurrence and development as well as elucidation of their molecular biological characteristics. Recent studies have revealed RNA modifications as a key regulatory mechanism involved in tumorigenesis, tumor progression, immune regulation, and response to therapy. The present review discusses research advances on several RNA modifications involved in glioma progression and tumor microenvironment (TME) immunoregulation as well as in the development of adaptive drug resistance, summarizing current progress on major RNA modification targeting strategies.

IMMU-06. SYSTEMIC MRNA VACCINES RESET IMMUNOGENICITY AGAINST DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND DIPG remains a uniformly fatal disease in dire need of new therapies. There are currently no systemic therapies with proven efficacy against these tumors. To overcome these barriers, we developed a systemic mRNA lipid particle (LP) vaccine that localizes to tumors and reticuloendothelial (RE) organs to modulate both innate and adaptive immunity against poorly immunogenic tumors like DIPG. OBJECTIVE We sought to assess whether RNA-LPs encoding for model antigens (e.g. H3K27M) would reprogram innate immunity and simultaneously elicit sustained adaptive immunity against diffuse midline glioma (DMG). RESULTS RNA-LP encoding for model antigens elicit massive recruitment of nearly all monocytes and lymphocytes to RE organs secondary to a danger response mediated by release of orchestrated cytokines (IL-12, TNF-α, IFN-α) and chemokines (CCL2, CCL4, CXCL9-10). This corresponds to increases in absolute numbers of activated DCs and T cells in the RE organs of mice and reprogramming the glioma tumor microenvironment in canines (pet dogs with spontaneous disease). In neonatal mice inoculated midline with established murine K2 gliomas, we observed that RNA-LP vaccines encoding for H3K27M (beginning at ~day 30) elicit significant long-term survivorship, which appears curative in the bulk of animals treated. While H3K27M specific constructs appeared superior, we observed improved survivorship with irrelevant mRNA species (i.e. pp65 and GFP) suggesting these tumors to be particularly sensitive to innate immune modulation. In mice with DMGs, we observed clinical symptomatology of edema/hydrocephalus followed by improvement in many animals suggesting pseudoprogression from intratumoral inflammation and remodeling. CONCLUSION RNA-LPs reprogram the tumor microenvironment of poorly immunogenic tumors in effect making them ‘hot.’ Treatment responses in murine models of advanced DMGs are encouraging. We are advancing a final RNA-LP formulation for FDA-IND submission and early phase clinical trials for DIPG through multi-institutional consortia.

Interrogating drug action and immune response in organotypic glioma microenvironment.

2068 Background: The glioma tumor microenvironment is characteristic of a high level of heterogeneity and a profoundly immune suppressive phenotype as driven by the presence of glioma stem cells and abundant innate immune cells of the myeloid lineages, rendering glioblastomas (GBM) recalcitrant to conventional treatments and immunotherapies. To address the full complexity of the brain tumor with its diverse components, we have developed an organotypic slice culture system to overcome several limitations of the other preclinical models and allow interrogation of drug action and immunomodulatory agents in human GBM ex vivo. Methods: We performed extensive characterization of the organotypic glioma slice system and optimization of the ex vivo tissue culture conditions, and determined the longitudinal dynamics of slice cell viability, relative tumor versus immune cellularity, and responses to a selection of therapeutic agents and cytokines by multiplexed flow cytometry and single cell transcriptome (scRNA seq) profiling. Results: Single cell transcriptomic analysis showed that both tumor and immune cell heterogeneity were preserved ex vivo for the two-week observation time, which exhibited tumor-type specific gene expression profiles suggesting cooperative interactions among cell populations. Consistent with the findings in fresh tumor specimens and an immune suppressive microenvironment, we found a scarcity of T lymphocytes in IDH mutant gliomas, whereas abundant T cells were found in recurrent GBM slices that persisted ex vivo. Additional analyses revealed that T cell infiltration in GBM was associated with the mesenchymal-like molecular phenotype, which exhibited remarkable intratumor heterogeneity highlighting the presence of stem-like cells and a unique cell population expressing aberrant cancer genes and antigen presenting molecules. We further found that T cells in organotypic GBM slices acquired a potent effector phenotype in response to cytokine-induced reprogramming of microglia and tumor-associated macrophages. In addition, scRNA seq also revealed a population of cancer-associated fibroblast-like cells that are present in all tumors sequenced, which may function to mediate the interactions between immune and tumor cells as our data suggested. Conclusions: We demonstrated that the organotypic slice culture system we developed is compatible with genomic, pharmacological, and immunotherapeutic manipulations and provided data showing that organotypic slice culture preserves glioma microenvironment ex vivo allowing acquisition of crucial information of response of heterogeneous patient tumor tissue to the agent tested. This method represents a unique mechanism by which therapy development can be facilitated in an ex vivo setting.

Grade scoring system reveals distinct molecular subtypes and identifies KIF20A as a novel biomarker for predicting temozolomide treatment efficiency in gliomas.

The importance of molecular diagnostics is increasingly emphasized in the 2021 WHO guidelines for gliomas. There is considerable variability in molecular features and prognosis among glioma patients with the same pathological WHO grade. mRNA data and clinical information of human glioma patients were obtained from TCGA and CGGA databases, while expression profiles and TMZ resistance phenotypes of human glioma stem cells were acquired from the GEO database. Differentially expressed genes were identified across distinct WHO grades. Unsupervised clustering was performed on glioma patients based on DEG expression profiles. The Boruta algorithm was employed to identify feature genes for distinct molecular subtypes, and PCA was used to reduce the dimensionality of the feature gene expression data. Grade scores for each sample were calculated and correlated with patients' clinical molecular pathological features and immune microenvironment. Gene set enrichment analysis identified grade score-related functional pathways. Weighted gene co-expression network analysis identified grade score-associated biomarkers. The impact of the hub gene on malignant glioma behavior was validated through in vitro experiments, including CCK-8, EdU, colony formation, Transwell, wound healing, and immunofluorescence assays. A total of 672 and 687 samples were screened from TCGA and CGGA databases, respectively, along with 6 control, 24 low-grade, and 40 glioblastoma samples from our hospital. Two robust gene clusters were identified based on the expression profiles of 4,476 DEGs among grades 2, 3, and 4 tissues, revealing distinct prognoses. The grade scores exhibited significant heterogeneity across different WHO grade samples, representing diverse immune microenvironments. Grade scores served as independent risk factors for predicting patient prognosis, with higher sensitivity than traditional biomarkers. KIF20A, identified as a grade score-related biomarker, was independently associated with glioma prognosis. Exclusively expressed in tumor cells, KIF20A knockdown significantly inhibited tumor growth, invasion, and EMT biological behavior in glioma cells. Furthermore, KIF20A could serve as a biological marker for predicting patient response to TMZ treatment. The grade scoring system enhances our understanding of the glioma tumor microenvironment. KIF20A, a novel biomarker for predicting TMZ treatment efficiency, influences malignant tumor behavior by affecting the EMT biological behavior of glioma cells.

Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas.

Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.

Dynamic change in Siglec-15 expression in peritumoral macrophages confers an immunosuppressive microenvironment and poor outcome in glioma.

Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) was reported to be a novel immune checkpoint molecule comparable to programmed cell death 1 ligand 1 (PD-L1). However, its expression profile and immunosuppressive mechanisms in the glioma tumor microenvironment have not yet been fully explored. To identify the expression profile and potential function of Siglec-15 in glioma tumor microenvironment. We investigated Siglec-15 and PD-L1 expression in tumor tissues from 60 human glioma patients and GL261 tumor models. Next, Siglec-15 knockout macrophages and mice were used to elucidate the immunosuppressive mechanism of Siglec-15 impacting macrophage function. Our results demonstrated that high levels of Siglec-15 in tumor tissues was positively correlated with poor survival in glioma patients. Siglec-15 was predominantly expressed on peritumoral CD68+ tumor-associated macrophages, which accumulated to the highest level in grade II glioma and then declined as grade increased. The Siglec-15 expression pattern was mutually exclusive with that of PD-L1 in glioma tissues, and the number of Siglec-15+PD-L1- samples (n = 45) was greater than the number of Siglec-15-PD-L1+ samples (n = 4). The dynamic change in and tissue localization of Siglec-15 expression were confirmed in GL261 tumor models. Importantly, after Siglec15 gene knockout, macrophages exhibited enhanced capacities for phagocytosis, antigen cross-presentation and initiation of antigen-specific CD8+ T-lymphocyte responses. Our findings suggested that Siglec-15 could be a valuable prognostic factor and potential target for glioma patients. In addition, our data first identified dynamic changes in Siglec-15 expression and distribution in human glioma tissues, indicating that the timing of Siglec-15 blockade is critical to achieve an effective combination with other immune checkpoint inhibitors in clinical practice.

Ubiquitin-proteasome system-mediated ubiquitination modification patterns and characterization of tumor microenvironment infiltration, stemness and cellular senescence in low-grade glioma

The Ubiquitin-proteasome system (UPS) performs a crucial role in immune activation and tumorigenesis. Nevertheless, the comprehensive role of the ubiquitin-proteasome system in the low-grade glioma (LGG) tumor microenvironment (TME) remains unknown. Ubiquitination modification patterns in LGG patients and corresponding characteristics of tumor immune traits, CSC stemness, and cellular senescence were evaluated via a comprehensive analysis of 20 ubiquitination modification regulators. For quantification of the ubiquitination modification status of individual patients, the UM-score was constructed and associated with TME characteristics, clinical features, cancer stem cell stemness, cellular senescence, prognosis, and immunotherapy efficacy. We identified that alterations in multiple ubiquitination regulators are linked to patient survival and the shaping of the tumor microenvironment. We found two different styles of ubiquitination modification in patients with low-grade glioma (immune-inflamed differentiation and immune-exclude dedifferentiation), characterized by high and low UM-score, and the two regulatory patterns of ubiquitination modification on immunity, stemness feature, and cellular senescence. We demonstrate that the UM-score could forecast the subtype of LGG, the immunologic infiltration traits, the biological process, the stemness feature, and the cellular senescence trait. Notably, the UM-score was related to immunotherapeutic efficacy, implying that modifying ubiquitination modification patterns by targeting ubiquitination modification regulators or ubiquitination modification pattern signature genes to reverse unfavorable TME properties will provide new insights into cancer immunotherapy. This research indicated that the ubiquitin-proteasome system is crucial in the formation of TME complexity and multiformity. The UM-score can determine ubiquitination modification status in individual patients, bringing about more personalized and effective immunotherapeutic tactics.

Abstract 2352: ALDOC interplays with KIAA1409 to reduce m6A modifications and cancer-associated fibroblast characteristics in gliomas

Abstract The abundance and regulatory mechanisms of tumor microenvironment in gliomas remain unclear. We have previously demonstrated that aldolase c (ALDOC) has tumor suppressor function and prognostic value in the progression of glioma. In this study, we used immune infiltration algorithms to identify the immune response events that ALDOC modulates in gliomas and found that they were particularly strongly associated with cancer-associated fibroblasts (CAFs). Our transcriptomic and proteomic profiles infer that ALDOC is involved in the methylation status of N6-methyladenosine (m6A) and binds to KIAA1429, which in turn affects the assembly of the assembly of the m6A-METTL complex. We show that ALDOC can interact with KIAA1429 and trap it in the cytoplasm and then interfere with the modification of m6A. In malignant cells and ALDOC knockdown models, we observed loss of ALDOC function, KIAA1429 was responsible for the ‘writer’ of m6A and stabilized expression levels of various CAF-related features. Through the MeRIP-Seq/m6A-seq approach, we found that the RNA-binding protein, IGF2BP2, can be directly stabilized with multiple CAF-related genes. We examined ALDOC and KIAA1429, CAF-related genes (FAP, α-SMA, S100A4 and VIM) in available cohorts and tissue microarrays and were statistically inversely correlated. Furthermore, ALDOC colocalized with KIAA1429 and CAF genes in the surrounding microenvironment was significantly reduced in tissue sections from orthotopic animal models by multiplex immunohistochemistry. Keywords: Aldolase C, m6A modification, cancer-associated fibroblasts, gliomas Citation Format: Chien-Hsiu Li, Ming-Hsien Chan, Yu-Chan Chang. ALDOC interplays with KIAA1409 to reduce m6A modifications and cancer-associated fibroblast characteristics in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2352.

Characterization of purinergic signaling in tumor-infiltrating lymphocytes from lower- and high-grade gliomas.

Malignant gliomas are highly heterogeneous glia-derived tumors that present an aggressive and invasive nature, with a dismal prognosis. The multi-dimensional interactions between glioma cells and other tumor microenvironment (TME) non-tumoral components constitute a challenge to finding successful treatment strategies. Several molecules, such as extracellular purines, participate in signaling events and support the immunosuppressive TME of glioma patients. The purinergic signaling and the ectoenzymes network involved in the metabolism of these extracellular nucleotides are still unexplored in the glioma TME, especially in lower-grade gliomas (LGG). Also, differences between IDH-mutant (IDH-Mut) versus wild-type (IDH-WT) gliomas are still unknown in this context. For the first time, to our knowledge, this study characterizes the TME of LGG, high-grade gliomas (HGG) IDH-Mut, and HGG IDH-WT patients regarding purinergic ectoenzymes and P1 receptors, focusing on tumor-infiltrating lymphocytes. Here, we show that ectoenzymes from both canonical and non-canonical pathways are increased in the TME when compared to the peripheral blood. We hypothesize this enhancement supports extracellular adenosine generation, hence increasing TME immunosuppression.

Molecular subtypes based on PANoptosis-related genes and tumor microenvironment infiltration characteristics in lower-grade glioma.

The growth of cancer, the effectiveness of treatment, and prognosis are all closely related to PANoptosis (include pyroptosis, apoptosis, and necroptosis). It remains unclear whether PANoptosis genes (PANGs) may contribute to lower-grade glioma (LGG) tumor microenvironment (TME). In this study, we collected 1203 LGG samples from three public databases and reported that PANoptosis involves TME interaction and prognosis. Firstly, we provided a comprehensive review of the pan-cancer landscape of PANGs in terms of expression characteristics, prognostic value, mutational profile, and pathway regulation. Then, we identified two distinct PANclusters, each with its own molecular, clinical, and immunological profile. We then developed a scoring system for LGG patients called PANscore. As well as investigating immune characteristics, tumor mutational characteristics, and drug sensitivity, we examined the differences between groups with high PANscores and those with low PANscores. Based on this PANscore and clinicopathological variables, an instant nomogram for predicting clinical survival in LGG patients was developed. Our thorough examination of PANGs in LGG revealed their probable function in TME, as well as their clinicopathological characteristics and prognosis. These discoveries could deepen our comprehension of PANGs in LGG and provide doctors fresh perspectives on how to forecast prognosis and create more efficient, individualized treatment plans.

Glioma-associated microglia/macrophages (GAMs) in glioblastoma: Immune function in the tumor microenvironment and implications for immunotherapy.

Glioma is a mixed solid tumor composed of neoplastic and non-neoplastic components. Glioma-associated macrophages and microglia (GAMs) are crucial elements of the glioma tumor microenvironment (TME), regulating tumor growth, invasion, and recurrence. GAMs are also profoundly influenced by glioma cells. Recent studies have revealed the intricate relationship between TME and GAMs. In this updated review, we provide an overview of the interaction between glioma TME and GAMs based on previous studies. We also summarize a series of immunotherapies targeting GAMs, including clinical trials and preclinical studies. Specifically, we discuss the origin of microglia in the central nervous system and the recruitment of GAMs in the glioma background. We also cover the mechanisms through which GAMs regulate various processes associated with glioma development, such as invasiveness, angiogenesis, immunosuppression, recurrence, etc. Overall, GAMs play a significant role in the tumor biology of glioma, and a better understanding of the interaction between GAMs and glioma could catalyze the development of new and effective immunotherapies for this deadly malignancy.

Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4+ and CD8+ Tcells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression.

Systematic analysis identifies REST as an oncogenic and immunological biomarker in glioma

The repressor element 1 silencing transcription factor (REST) has been proposed to function as a transcription factor to silence gene transcription by binding to repressor element 1 (RE1), a highly conserved DNA motif. The functions of REST in various tumors have been studied, but its role and correlation with immune cell infiltration remains uncertain in gliomas. REST expression was analyzed in datasets of The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) and validated by the Gene Expression Omnibus and Human Protein Atlas databases. The clinical prognosis of REST was evaluated by clinical survival data of TCGA cohort and validated by Chinese Glioma Genome Atlas cohort. MicroRNAs (miRNAs) contributing to REST overexpression in glioma were identified by a combination of a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. The correlations between immune cell infiltration level and REST expression were analyzed by TIMER2 and GEPIA2 tools. Enrichment analysis of REST was performed using STRING and Metascape tools. The expression and function of predicted upstream miRNAs at REST and their association with glioma malignancy and migration were also confirmed in glioma cell lines. REST was highly expressed and associated with poorer overall survival and disease-specific survival in glioma and some other tumors. MiR-105-5p and miR-9-5p were identified as the most potential upstream miRNAs of REST in glioma patient cohort and experiments in vitro. REST expression was positively correlated with infiltration of immune cells and the expression of immune checkpoints such as PD1/PD-L1 and CTLA-4 in glioma. Furthermore, histone deacetylase 1 (HDAC1) was a potential REST-related gene in glioma. Enrichment analysis of REST found chromatin organization and histone modification were the most significant enriched terms, and Hedgehog-Gli pathway might be involved in the effect of REST on the pathogenesis of glioma. Our study suggests REST to be an oncogenic gene and the biomarker of poor prognosis in glioma. High REST expression might affect the tumor microenvironment of glioma. More basic experiments and large clinical trials aimed at the carcinogenetic study of REST in glioma will be needed in the future.

Tumor Microenvironment in Gliomas: A Treatment Hurdle or an Opportunity to Grab?

Gliomas are the most frequent central nervous system (CNS) primary tumors. The prognosis and clinical outcomes of these malignancies strongly diverge according to their molecular alterations and range from a few months to decades. The tumor-associated microenvironment involves all cells and connective tissues surrounding tumor cells. The composition of the microenvironment as well as the interactions with associated neoplastic mass, are both variables assuming an increasing interest in these last years. This is mainly because the microenvironment can mediate progression, invasion, dedifferentiation, resistance to treatment, and relapse of primary gliomas. In particular, the tumor microenvironment strongly diverges from isocitrate dehydrogenase (IDH) mutated and wild-type (wt) tumors. Indeed, IDH mutated gliomas often show a lower infiltration of immune cells with reduced angiogenesis as compared to IDH wt gliomas. On the other hand, IDH wt tumors exhibit a strong immune infiltration mediated by several cytokines and chemokines, including CCL2, CCL7, GDNF, CSF-1, GM-CSF, etc. The presence of several factors, including Sox2, Oct4, PD-L1, FAS-L, and TGF β2, also mediate an immune switch toward a regulatory inhibited immune system. Other important interactions are described between IDH wt glioblastoma cells and astrocytes, neurons, and stem cells, while these interactions are less elucidated in IDH-mutated tumors. The possibility of targeting the microenvironment is an intriguing perspective in terms of therapeutic drug development. In this review, we summarized available evidence related to the glioma microenvironment, focusing on differences within different glioma subtypes and on possible therapeutic development.

IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM

IntroductionThe immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive...

Transcription factor ZBTB42 is a novel prognostic factor associated with immune cell infiltration in glioma.

Background: ZBTB42 is a transcription factor that belongs to the ZBTB transcript factor family and plays an important role in skeletal muscle development. Dysregulation of ZBTB42 expression can lead to a variety of diseases. However, the function of ZBTB42 in glioma development has not been studied by now. Methods: We analyzed the expression of ZBTB42 in LGG and GBM via the The Cancer Genome Atlas CGA and Chinese Glioma Genome Atlas database. Gene Ontology, KEGG, and GSVA analyses were performed to illustrate ZBTB42-related pathways. ESTIMATE and CIBERSORT were applied to calculate the immune score and immune cell proportion in glioma. One-class logistic regression OCLR algorithm was used to study the stemness of glioma. Multivariate Cox analysis was employed to detect the prognostic value of five ZBTB42-related genes. Results: Our results show that ZBTB42 is highly expressed in glioma and may be a promising prognostic factor for Low Grade Glioma and GBM. In addition, ZBTB42 is related to immune cell infiltration and may play a role in the immune suppression microenvironment. What's more, ZBTB42 is correlated with stem cell markers and positively associated with glioma stemness. Finally, a five genes nomogram based on ZBTB42 was constructed and has an effective prognosis prediction ability. Conclusion: We identify that ZBTB42 is a prognostic biomarker for Low Grade Glioma and GBM and its function is related to the suppressive tumor microenvironment and stemness of glioma.