Abstract
Background: Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to the intrinsic radio- and chemo-resistance. As an essential part of tumor immunotherapy for adjunct, therapeutic tumor vaccines have been effective against multiple solid cancers, while their efficacy against GBM remains undefined. Therefore, this study aims to find the possible tumor antigens of GBM and identify the suitable population for cancer vaccination through immunophenotyping.Method: The genomic and responding clinical data of 169 GBM samples and five normal brain samples were obtained from The Cancer Genome Atlas (TCGA). The mRNA_seq data of 940 normal brain tissue were downloaded from Genotype-Tissue Expression (GTEx). Potential GBM mRNA antigens were screened out by differential expression, copy number variant (CNV), and mutation analysis. K-M survival and Cox analysis were carried out to investigate the prognostic association of potential tumor antigens. Tumor Immune Estimation Resource (TIMER) was used to explore the association between the antigens and tumor immune infiltrating cells (TIICs). Immunophenotyping of 169 samples was performed through consensus clustering based on the abundance of 22 kinds of immune cells. The characteristics of the tumor immune microenvironment (TIME) in each cluster were explored through single-sample gene set enrichment analysis based on 29 kinds of immune-related hallmarks and pathways. Weighted gene co-expression network analysis (WGCNA) was performed to cluster the genes related to immune subtypes. Finally, pathway enrichment analyses were performed to annotate the potential function of modules screened through WGCNA.Results: Two potential tumor antigens selected were significantly positively associated with the antigen-presenting immune cells (APCs) in GBM. Furthermore, the expression of antigens was verified at the protein level by Immunohistochemistry. Two robust immune subtypes, immune subtype 1 (IS1) and immune subtype 2 (IS2), representing immune status “immune inhibition” and “immune inflamed”, respectively, had distinct clinical outcomes in GBM.Conclusion: ARPC1B and HK3 were potential mRNA antigens for developing GBM mRNA vaccination, and the patients in IS2 were considered the most suitable population for vaccination in GBM.
Highlights
Grade IV glioblastoma (GBM), known as the most lethal type of brain cancer, was highly aggressive, and the survival rate of patients with GBM was extremely low (Li et al, 2021)
To identify the potential antigens of GBM, we first screened out 11,528 genes with a significantly different copy number variations (CNVs) and 12,684 mutant genes in the GBM samples, respectively
Since tumor-associated antigens (TAAs) are considered overexpressed in tumors, we identified 12,015 overexpressed genes in GBM compared to normal brain tissues
Summary
Grade IV glioblastoma (GBM), known as the most lethal type of brain cancer, was highly aggressive, and the survival rate of patients with GBM was extremely low (Li et al, 2021). Despite adjuvant radiotherapy and chemotherapy, the clinical outcome of GBM patients remains miserable with a high recurrence rate for the resistance of GBM to chemotherapies (Quick et al, 2010). Compared with the first four types, mRNA vaccines are highly feasible for targeting tumor-specific antigens and promising immunotherapy strategies in clinical treatment (Mockey et al, 2007; Kaitsuka and Tomizawa, 2015; Nguyen et al, 2019). As an essential part of tumor immunotherapy for adjunct, therapeutic tumor vaccines have been effective against multiple solid cancers, while their efficacy against GBM remains undefined. This study aims to find the possible tumor antigens of GBM and identify the suitable population for cancer vaccination through immunophenotyping
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