Abstract

BackgroundImmune checkpoints target regulatory pathways in T cells that enhance antitumor immune responses and elicit durable clinical responses. As a novel immune checkpoint, CD96 is an attractive key target for cancer immunotherapy. However, there has been no integrative investigation of CD96 in glioma. Our study explored the relationship between CD96 expression and clinical prognosis in glioma.MethodsRNA and clinical data for a total of 1,001 samples were included in this study, including 325 samples from the Chinese Glioma Genome Atlas (CGGA) database and 676 samples from The Cancer Genome Atlas (TCGA) dataset. The R programming language was employed to perform statistical analysis and draw figures.ResultsCD96 had a consistently positive relationship with glioblastoma and was highly enriched in IDH-wildtype and mesenchymal subtype glioma. Gene ontology enrichment and gene set variation analysis analyses suggested that CD96 was mostly involved in immune functions and was especially related to T cell-mediated immune response in glioma. Subsequent immune infiltration analysis showed that CD96 was positively correlated with infiltrating levels of CD4 + T and CD8 + T cells, macrophages, neutrophils, and DCs in glioblastoma multiforme and low-grade glioma. Additionally, CD96 was tightly associated with other immune checkpoints, including PD-1, CTLA-4, TIGIT, and TIM-3. Univariate and multivariate Cox analysis demonstrated that CD96 acts as an independent indicator of poor prognosis in glioma.ConclusionCD96 expression was increased in malignant phenotype and negatively associated with overall survival in glioma. CD96 also showed a positive correlation with other immune checkpoints, immune response, and inflammatory activity. Our findings indicate that CD96 is a promising clinical target for further immunotherapeutic use in glioma patients.

Highlights

  • The most prevalent and devastating primary intracranial tumor, glioma, and especially glioblastoma multiforme (GBM, World Health Organization. 1http (WHO) grade IV), are characterized by heterogeneity and extensive invasion, with high recurrence and fatality rate (Jiang et al, 2016; Louis et al, 2016; Van Meir et al, 2010)

  • The results revealed that CD96 expression was comparatively upregulated in higher-grade gliomas

  • We found that CD96 was consistently enriched in Isocitrate dehydrogenase (IDH)-wildtype (IDHWT) in both the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases (Figures 1E,F)

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Summary

Introduction

The most prevalent and devastating primary intracranial tumor, glioma, and especially glioblastoma multiforme (GBM, WHO grade IV), are characterized by heterogeneity and extensive invasion, with high recurrence and fatality rate (Jiang et al, 2016; Louis et al, 2016; Van Meir et al, 2010). In melanoma and non-small-cell lung cancer, immune checkpoint inhibitors like target programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) have been exploited and successfully applied in the clinic (Topalian et al, 2012; Wang et al, 2016; Huang et al, 2017), whereas many glioma patients are refractory to current immunotherapy, which arouses our interest in identifying additional immune checkpoints to enhance the therapeutic efficacy in glioma (Reardon et al, 2014; Huang et al, 2017). A novel immune checkpoint receptor target, CD96, has recently entered the limelight in current cancer immunotherapies shown to inhibit natural killer (NK) cells (Georgiev et al, 2018). Our study explored the relationship between CD96 expression and clinical prognosis in glioma

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