Immune Checkpoint Inhibitors in Human Glioma Microenvironment

Ghouzlani, Amina; Kandoussi, Sarah; Tall, Mariam; Reddy, Konala Priyanka; Rafii, Soumaya; Badou, Abdallah

doi:10.3389/fimmu.2021.679425

Cited by 110 publications

(98 citation statements)

References 89 publications

(105 reference statements)

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“…Moreover, the co-expression of PD-1 with other inhibitory receptors, such as PDL-1, TIM-3, LAG3, and CTLA-4, induces effector T cell exhaustion (73,74). It has also been reported that the PD-1/ PDL-1 pathway is significantly correlated with the most aggressive histological subtype of glioma (75,76). This could reflect the importance of the complex mechanisms established by the tumor microenvironment to suppress the antitumor immune response.…”

Section: Discussionmentioning

confidence: 97%

Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades

et al. 2021

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BackgroundGlioma is the most common type of primary brain tumor in adults. Patients with the most malignant form have an overall survival time of <16 months. Although considerable progress has been made in defining the adapted therapeutic strategies, measures to counteract tumor escape have not kept pace, due to the developed resistance of malignant glioma. In fact, identifying the nature and role of distinct tumor-infiltrating immune cells in glioma patients would decipher potential mechanisms behind therapy failure.MethodsWe integrated into our study glioma transcriptomic datasets from the Cancer Genome Atlas (TCGA) cohort (154 GBM and 516 LGG patients). LM22 immune signature was built using CIBERSORT. Hierarchical clustering and UMAP dimensional reduction algorithms were applied to identify clusters among glioma patients either in an unsupervised or supervised way. Furthermore, differential gene expression (DGE) has been performed to unravel the top expressed genes among the identified clusters. Besides, we used the least absolute shrinkage and selection operator (LASSO) and Cox regression algorithm to set up the most valuable prognostic factor.ResultsOur study revealed, following gene enrichment analysis, the presence of two distinct groups of patients. The first group, defined as cluster 1, was characterized by the presence of immune cells known to exert efficient antitumoral immune response and was associated with better patient survival, whereas the second group, cluster 2, which exhibited a poor survival, was enriched with cells and molecules, known to set an immunosuppressive pro-tumoral microenvironment. Interestingly, we revealed that gene expression signatures were also consistent with each immune cluster function. A strong presence of activated NK cells was revealed in cluster 1. In contrast, potent immunosuppressive components such as regulatory T cells, neutrophils, and M0/M1/M2 macrophages were detected in cluster 2, where, in addition, inhibitory immune checkpoints, such as PD-1, CTLA-4, and TIM-3, were also significantly upregulated. Finally, Cox regression analysis further corroborated that tumor-infiltrating cells from cluster 2 exerted a significant impact on patient prognosis.ConclusionOur work brings to light the tight implication of immune components on glioma patient prognosis. This would contribute to potentially developing better immune-based therapeutic approaches.

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Section: Discussionmentioning

confidence: 97%

Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades

et al. 2021

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“…Finally, spearman correlation analysis was used to access the relationship between risk scores and the expression levels of common immune checkpoints, including programmed cell death 1 (PD1), programmed cell death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4(CTLA-4), Lymphocyte Activating 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), B7-H3(CD276), T-cell immunoglobulin and ITIM domain (TIGIT) ( Ghouzlani et al, 2021 ; Yang et al, 2022 ) and two newly biomarkers APOBEC3B and TNFSF13 ( Zhang et al, 2021a ; Zhang et al, 2021c ). Then, we investigated the role of PRGs signature in predicting glioma immunotherapeutic response by the tumor immune dysfunction and exclusion (TIDE) algorithm ( http://tide.dfci.harvard.edu ).…”

Section: Methodsmentioning

confidence: 99%

“…Over the past decades, numerous therapies have been developed to treat cancers; however, few of them could effectively use in glioma. Despite the blood-brain barrier, unique structure in the CNS ( Oberoi et al, 2015 ), glioma cells adapted various strategies to escape the immune system also play an essential role ( Ghouzlani et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Pyroptosis-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Glioma

Zhang

Yang

et al. 2022

Front. Cell Dev. Biol.

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Objective: Gliomas are the most common primary tumors in the central nervous system with a bad prognosis. Pyroptosis, an inflammatory form of regulated cell death, plays a vital role in the progression and occurrence of tumors. However, the value of pyroptosis related genes (PRGs) in glioma remains poorly understood. This study aims to construct a PRGs signature risk model and explore the correlation with clinical characteristics, prognosis, tumor microenviroment (TME), and immune checkpoints.Methods: RNA sequencing profiles and the relevant clinical data were obtained from the Chinese Glioma Genome Atlas (CGGA), the Cancer Genome Atlas (TCGA), the Repository of Molecular Brain Neoplasia Data (REMBRANDT), and the Genotype-Tissue Expression Project (GTEx-Brain). Then, the differentially expressed pyroptosis related genes (PRGs) were identified, and the least absolute shrinkage and selection operator (LASSO) and mutiCox regression model was generated using the TCGA-train dataset. Then the expression of mRNA and protein levels of PRGs signature was detected through qPCR and human protein atlas (HPA). Further, the predictive ability of the PRGs-signature, prognostic analysis, and stratification analysis were utilized and validated using TCGA-test, CGGA, and REMBRANDT datasets. Subsequently, we constructed the nomogram by combining the PRGs signature and other key clinical features. Moreover, we used gene set enrichment analysis (GSEA), GO, KEGG, the tumor immune dysfunction and exclusion (TIDE) single-sample GSEA (ssGSEA), and Immunophenoscore (IPS) to determine the relationship between PRGs and TME, immune infiltration, and predict the response of immune therapy in glioma.Results: A four-gene PRGs signature (CASP4, CASP9, GSDMC, IL1A) was identified and stratified patients into low- or high-risk group. Survival analysis, ROC curves, and stratified analysis revealed worse outcomes in the high-risk group than in the low-risk group. Correlation analysis showed that the risk score was correlated with poor disease features. Furthermore, GSEA and immune infiltrating and IPS analysis showed that the PRGs signature could potentially predict the TME, immune infiltration, and immune response in glioma.Conclusion: The newly identified four-gene PRGs signature is effective in diagnosis and could robustly predict the prognosis of glioma, and its impact on the TME and immune cell infiltrations may provide further guidance for immunotherapy.

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“…In the past few years, a collection of data has clarified the crucial role of the immune checkpoints in regulating the immune response in different cancer types. However, research on immunotherapy of glioma has extended in an exponential manner 4 – 7 . The majority of gliomas is obstinate to usual immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis

Ghouzlani

Lakhdar

Rafii

et al. 2021

Sci Rep

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In human gliomas, anti-tumor T cell responses are inhibited through induction of local and systemic immunosuppression. Immune checkpoint blockade is proving to be a success in several types of cancers. However, many studies reported that the treatment of glioblastoma patients with anti-CTLA-4 or anti-PD-1 has no survival benefit compared to standard chemotherapy. This study aimed to investigate the expression and role of VISTA, a newly described immune checkpoint regulator, in human gliomas. mRNA expression was assessed in a total of 87 samples from glioma patients. 57 glioma tissues were taken at different grades. 20 peripheral blood mononuclear cells (PBMC) samples were taken before surgery and ten after surgery, all from the same set of patients. As for the control, ten specimens of PBMC were taken from healthy donors. Protein expression using immunohistochemistry was performed for 30 patients. The Cancer Genome Atlas (TCGA) data set, was also used to investigate VISTA expression through analysis of RNA-seq data of 667 glioma patients. In the Moroccan cohort, VISTA gene expression was significantly upregulated in glioma tissues related to PBMC of healthy donors. This high expression was specific to patient tissues since VISTA expression in PBMC was low when assessed either before or after surgery. Besides, VISTA exhibited higher expression levels in grade III/IV relative to grade I/II glioma patients. Interestingly, VISTA correlated positively with PD-1 expression. PD-1 also showed elevated expressions in higher glioma grades. The TCGA cohort corroborated these observations. Indeed, VISTA was also found to be strongly expressed in high grades. It was positively correlated with other critical immune checkpoints. Finally, increased VISTA transcript levels were associated with weak overall survival of glioma patients. Our study highlighted a correlation between high levels of VISTA expression and poor prognosis in glioma patients. VISTA might be involved in glioma progression and could be considered as a possible new therapeutic target, especially in advanced gliomas.

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Immune Checkpoint Inhibitors in Human Glioma Microenvironment

Cited by 110 publications

References 89 publications

Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades

Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades

Pyroptosis-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Glioma

The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis

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