Author:
Wang Qianghu,Hu Xin,Hu Baoli,Muller Florian,Kim Hoon,Squatrito Massimo,Millelsen Tom,Scarpace Lisa,Barthel Floris,Lin Yu-Hsi,Satani Nikunj,Martinez-Ledesma Emmanuel,Chang Edward,Olar Adriana,Wang Guocan,deCarvalho Ana C.,Eskilsson Eskil,Zheng Siyuan,Heimberger Amy B.,Sulman Erik P.,Nam Do-Hyun,Verhaak Roel G.W.
Abstract
SummaryWe 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/.SignificanceIDH 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
Publisher
Cold Spring Harbor Laboratory
Cited by
7 articles.
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