Abstract
A major challenge for successful immunotherapy against glioma is the identification and characterization of validated targets. We have taken a bioinformatics approach towards understanding the biological context of IL-13 receptor α2 (IL13Rα2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13Rα2 expression increases with glioma malignancy grade, and expression for high-grade tumors is bimodal, with approximately 58% of WHO grade IV gliomas over-expressing this receptor. By several measures, IL13Rα2 expression in patient samples and low-passage primary glioma lines most consistently correlates with the expression of signature genes defining mesenchymal subclass tumors and negatively correlates with proneural signature genes as defined by two studies. Positive associations were also noted with proliferative signature genes, whereas no consistent associations were found with either classical or neural signature genes. Probing the potential functional consequences of this mesenchymal association through IPA analysis suggests that IL13Rα2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13Rα2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13Rα2 in the top ~1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13Rα2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13Rα2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials.
Highlights
Malignant gliomas are highly aggressive and uniformly lethal human brain cancers
Further we find that IL-13 receptor α2 (IL13Rα2) expression increases with glioma malignancy grade, is linked to activated immune pathways by Ingenuity Pathway Analysis (IPA) analysis, and is a prognostic indicator of poor patient survival
Astrocytomas did not exhibit a statistically significant difference in IL13Rα2 expression from oligoastrocytomas and oligodendrogliomas (p=0.69, 2-way ANOVA with linear contrast to account for batch effects due to study) (Figure 1B), and no discernible differences were observed between the three histological subtypes (p=0.83, 2way ANOVA to account for batch effects due to study)
Summary
Malignant gliomas are highly aggressive and uniformly lethal human brain cancers These tumors are histologically and molecularly diverse, exhibiting heterogeneity both between patients and within individual tumors [1,2]. Verhaak et al [5] combined genomic and expression data from The Cancer Genome Atlas (TCGA) in an unsupervised analysis to define four distinct glioblastoma subclasses: proneural, neural, classical and mesenchymal These descriptions of tumor molecular heterogeneity provide the opportunity to evaluate potential therapeutic targets in relation to underlying tumor biology. Further we find that IL13Rα2 expression increases with glioma malignancy grade, is linked to activated immune pathways by IPA analysis, and is a prognostic indicator of poor patient survival These observations enhance understanding of IL13Rα2 as a therapeutic target and provide guidance for the design of patient specific therapies tailored for optimal therapeutic responses
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