Abstract B82: Immune signatures of glioblastoma subtypes: Extrapolation from the Cancer Genome Atlas.
Authors: Doucette Tiffany , Rao Ganesh , Aldape Kenneth , Wei Jun , Dziurzynski Kristine , Rao Arvind , Shen Li , Gilbert Mark R. , Heimberger Amy B. 
Published: August 2014

A major obstacle to the treatment of gliomas is the subversion of the immune system by the tumor to facilitate proliferation and malignant degeneration of tumor cells. Immune suppression is thought to play a major role in the aggressive nature of gliomas and their resistance to current therapies. Genomic profiling of glioblastomas (GBMs) has shown that at least four genotypic subtypes exist, with two being dominant (proneural and mesenchymal), each correlating with significant differences in patient survival. Despite a marked immunosuppressive microenvironment, a retrospective analysis of a dendritic cell immunotherapy clinical trial demonstrated that patients with the mesenchymal subtype were more likely to be clinical responders to immunomodulatory treatments. Although this finding tends to contradict what is thought about the immune suppressive nature of mesenchymal gliomas with respect to aggressiveness and poor patient survival, it suggests that mesenchymal gliomas may be more immunogenic and more responsive to immunotherapy. We analyzed mRNA expression levels of immune system genes relative to the other genes among the various glioblastoma subtypes using the Cancer Genome Atlas (TCGA) database to ascertain if there are alterations in antigen expression, the pattern of immune suppression, and effector response genes within glioblastoma subtypes that accounts for this apparent paradox. The glioblastoma cancer study set from the TCGA database of defined glioblastoma subtypes of proneural (n=56), mesenchymal (n=56), classical (n=54) and neural (n=29) was used as the source data available through the open access cBio Cancer Genomics Portal at www.cbioportal.org. To analyze mRNA expression of a comprehensive list of immune-associated genes in the four subtypes of glioma, the z-score for all genes (the number of standard deviations above the mean expression level of the selected gene) was set to &gt; 1 for each of the subtypes (e.g.: IL10: EXP&gt;1). Our results demonstrate a marked and preferential enrichment of genes associated with antitumor proinflammatory responses, including both adaptive and innate immunity as determined by mRNA overexpression of immune effector-associated genes in the mesenchymal subtype of glioma. This analysis also demonstrated an association of mRNA expression of immune suppression-associated genes such as PD-L1, CTLA-4, IL-10, and TGF-β, within the mesenchymal subtype. Furthermore, distinct glioma antigens demonstrated preferential expression within distinct subtypes. Cumulatively, our data suggest that analysis of these selected immune effector and suppressor genes may provide a way to programmatically prioritize different types of potentially competing immune therapeutic strategies and rapidly assess the prognostic impact of select genes on patient outcome. Additionally, these results may help to identify subsets of patients that may be particularly responsive to a particular strategy and thus selectively enrich for potential responders during early or small-scale clinical trials.

Citation Format: Tiffany Doucette, Ganesh Rao, Kenneth Aldape, Jun Wei, Kristine Dziurzynski, Arvind Rao, Li Shen, Mark R. Gilbert, Amy B. Heimberger. Immune signatures of glioblastoma subtypes: Extrapolation from the Cancer Genome Atlas. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B82.