Abstract
Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Gene expression profiling of GBM has revealed clinically relevant tumor subtypes, and this provides exciting opportunities to better understand disease pathogenesis. Results from an increasing number of studies demonstrate a role for the immune response in cancer progression, yet it is unclear how the immune response differs across tumor subtypes and how it affects outcome. Utilizing gene expression data from The Cancer Genome Atlas Project and the Gene Expression Omnibus database, we demonstrate an enrichment of immune response-related gene expression in the mesenchymal subtype of adult GBM (n = 173) and pediatric high-grade gliomas (n = 53). In an independent cohort of pediatric astrocytomas (n = 24) from UCSF, we stratified tumors into subtypes and confirmed these findings. Using novel immune cell-specific gene signatures we demonstrate selective enrichment of microglia/macrophage-related genes in adult and pediatric GBM tumors of the mesenchymal subtype. Furthermore, immunostaining of adult GBM tumors showed significantly higher cell numbers of microglia/macrophages in mesenchymal versus non-mesenchymal tumors (p = 0.04). Interestingly, adult GBM tumors with the shortest survival had significant enrichment of microglia/macrophage-related genes but this was not true for pediatric GBMs. Consistent with an association with poor outcome, immune response-related genes were highly represented in an adult poor prognosis gene signature, with the expression of genes related to macrophage recruitment and activation being most strongly associated with survival (p<0.05) using CoxBoost multivariate modeling. Using a microglia/macrophage high gene signature derived from quantification of tumor-infiltrating cells in adult GBM, we identified enrichment of genes characteristic of CD4 T cells, granulocytes, and microglia/macrophages (n = 573). These studies support a role for the immune response, particularly the microglia/macrophage response, in the biology of an important subset of GBM. Identification of this subset may be important for future therapeutic stratification.
Highlights
Glioblastoma (GBM), WHO grade IV astrocytoma, is a highly malignant disease with a poor prognosis despite aggressive treatment strategies [1]
48% of the enriched gene sets in the mesenchymal subtype were related to immune response processes, and included gene sets associated with development of the immune system, lymphocyte activation, response to infection or injury, and the adaptive immune response
Validation of the model in the independent data set resulted in a low Brier Score of 0.0793, demonstrating the strength of the model and the association between immune response gene expression and poor prognosis. To assess if these survival-related immune response genes may be expressed by the microglia/macrophage population within the tumor mass we examined gene expression profiling data from tumor-associated cells enriched for microglia/macrophages compared with bulk tumor from a single GBM sample [30]
Summary
Glioblastoma (GBM), WHO grade IV astrocytoma, is a highly malignant disease with a poor prognosis despite aggressive treatment strategies [1]. Results from molecular profiling studies of GBM suggest that stratification of these tumors into clinically relevant subtypes will lead to improved therapy outcomes as a result of individualizing treatment based on tumor molecular signatures. GBM is the most common primary malignant brain tumor. High-grade astrocytomas, including GBM, are less common, comprising 8–12% of central nervous system (CNS) malignancies, but are heterogeneous and present with a dismal outcome [2]. The mesenchymal GBM subtype is associated with reduced survival [4], and it is characterized by upregulation of genes involved in tumor microenvironment interactions and processes [4,7,9,10]
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