RT Journal Article SR Electronic T1 Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment JF bioRxiv FD Cold Spring Harbor Laboratory SP 052076 DO 10.1101/052076 A1 Qianghu Wang A1 Xin Hu A1 Baoli Hu A1 Florian Muller A1 Hoon Kim A1 Massimo Squatrito A1 Tom Millelsen A1 Lisa Scarpace A1 Floris Barthel A1 Yu-Hsi Lin A1 Nikunj Satani A1 Emmanuel Martinez-Ledesma A1 Edward Chang A1 Adriana Olar A1 Guocan Wang A1 Ana C. deCarvalho A1 Eskil Eskilsson A1 Siyuan Zheng A1 Amy B. Heimberger A1 Erik P. Sulman A1 Do-Hyun Nam A1 Roel G.W. Verhaak YR 2016 UL http://biorxiv.org/content/early/2016/08/13/052076.abstract AB 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