Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

Abstract

Summary We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

“…A total of 2,551 genes were differentially expressed, including genes involved in glial differentiation (Table S1), and Olig2 + tumors showed an enrichment of OPCs versus astrocytic genes (Figure 1B and Table S2) (Zhang et al, 2014). We compared gene expression in Olig2 + and Olig2 − mouse tumors with human OD and subtypes of GBM (Tirosh et al, 2016; Verhaak et al, 2010; Wang et al, 2017). As shown (Figures S1F, 1G, and Table S2), clustering analysis of differentially upregulated genes in Olig2 + (versus Olig2 − ) tumors indicated strongest association with human OD and proneural GBM gene profiles.…”

“…The p values were adjusted to account for multiple testing using the false discovery rate (FDR) approach, and probes with FDR p < 0.05 were considered to be differentially expressed. Genes up-regulated in Olig2 + tumors were compared to murine OPCs (versus astrocytic), human oligodendroglioma and GBM subtypes using published dataset (Tirosh et al, 2016; Verhaak et al, 2010; Wang et al, 2017; Zhang et al, 2014). Hierarchical clustering was performed using Gene Cluster 3.0 (de Hoon et al, 2004) and Treeview (Saldanha, 2004).…”

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

“…In our prior report, we found that GBM tumors of the mesenchymal subtype exhibited a statistically significant higher level of Fn14 expression when compared to the classical, neural, and proneural subtypes [4]. Of note, a recent report indicates that the neural subtype is not a tumor-intrinsic transcriptional subtype in IDH WT GBMs [44]. Here, we evaluated ~ 3× more tumor specimens and found that the Fn14 expression level was similar in the classical and mesenchymal subtypes although there was a trend toward higher expression in the mesenchymal tumors.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…26 The mutation status of gliomas is also associated with effects on the immune landscape of the tumor microenvironment, suggesting an impact on TAM protein expression in patient tumors. 27 A comparison of cores from IDH wild type and mutant tumors from our grade II-III TMA showed a slight increase in percentage of CD163 expressing cells in the IDH wild-type population (Figure 1E). Although it is tempting to speculate that CD163 infiltration may be associated with a poorer prognosis among these patients, the small sample size of wild type tumors (N = 3) precludes this conclusion and will be addressed in future studies evaluating a larger sample size.…”