TY - JOUR T1 - Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment JF - bioRxiv DO - 10.1101/052076 SP - 052076 AU - Qianghu Wang AU - Xin Hu AU - Baoli Hu AU - Florian Muller AU - Hoon Kim AU - Massimo Squatrito AU - Tom Millelsen AU - Lisa Scarpace AU - Floris Barthel AU - Yu-Hsi Lin AU - Nikunj Satani AU - Emmanuel Martinez-Ledesma AU - Edward Chang AU - Adriana Olar AU - Guocan Wang AU - Ana C. deCarvalho AU - Eskil Eskilsson AU - Siyuan Zheng AU - Amy B. Heimberger AU - Erik P. Sulman AU - Do-Hyun Nam AU - Roel G.W. Verhaak Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/08/13/052076.abstract N2 - Summary We leveraged IDH wild type glioblastomas and derivative neurospheres to define tumor-intrinsic transcription phenotypes. Transcriptomic multiplicity correlated with increased intratumoral heterogeneity and tumor microenvironment presence. In silico cell sorting demonstrated that M2 macrophages/microglia are the most frequent type of immune cells in the glioma microenvironment, followed by CD4 T lymphocytes and neutrophils. Hypermutation associated with CD8+ T cell enrichment. Longitudinal transcriptome analysis of 124 pairs of primary and recurrent gliomas showed expression subtype is retained in 53% of cases with no proneural to mesenchymal transition being apparent. Inference of the tumor microenvironment through gene signatures revealed a decrease in invading monocytes but a subtype dependent increase in M2 macrophages/microglia cells after disease recurrence. All expression datasets are accessible through http://recur.bioinfo.cnio.es/.Significance IDH wild type glioblastoma expression phenotypes have been related to tumor characteristics including genomic abnormalities and treatment response. We explored the intratumoral transcriptomic landscape, including a definition of tumor-intrinsic gene expression subtypes and how they relate to the different cellular components of the tumor immune environment. Comparison of matching primary and recurrent gliomas provided insights into the treatment-induced phenotypic tumor evolution. Proneural to mesenchymal transitions have long been suspected but were not apparent, while intratumoral heterogeneity was a predictor of subtype transition upon recurrence. Characterizing the evolving glioblastoma transcriptome en tumor microenvironment aids in designing more effective immunotherapy trials. Our study provides a comprehensive transcriptional and cellular landscape of IDH wild type GBM during treatment modulated tumor evolution.HighlightsNext generation GBM-intrinsic transcriptional subtypes: proneural, classical, mesenchymalM2 macrophages, CD4+ T-lymphocytes and neutrophils dominate glioblastoma microenvironmentSensitivity to radiotherapy may associate with M2 macrophage presenceCD8+ T cells are enriched in hypermutated GBMs at diagnosis and recurrence ER -