Glioma IL13Rα2 Is Associated with Mesenchymal Signature Gene Expression and Poor Patient Prognosis

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 alpha 2 (IL13R alpha 2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13R alpha 2 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, IL13R alpha 2 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 IL13R alpha 2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13R alpha 2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13R alpha 2 in the top similar to 1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13R alpha 2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13R alpha 2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials.