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bioRxiv · 10.1101/052076

Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment

Qianghu Wang·Xin Hu·Baoli Hu·Florian Muller·Hoon Kim·Massimo Squatrito·Tom Mikkelsen·Lisa Scarpace·Floris Barthel·Yu-Hsi Lin·Nikunj Satani·Emmanuel Martinez-Ledesma·Edward Chang·Adriana Olar·Guocan Wang·Ana C. deCarvalho·Eskil Eskilsson·Siyuan Zheng·Amy B. Heimberger·Erik P. Sulman·Do-Hyun Nam·Roel G.W. Verhaak
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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/.\n\nSignificanceIDH 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.\n\nHighlightsO_LINext generation GBM-intrinsic transcriptional subtypes: proneural, classical, mesenchymal\nC_LIO_LIM2 macrophages, CD4+ T-lymphocytes and neutrophils dominate glioblastoma microenvironment\nC_LIO_LISensitivity to radiotherapy may associate with M2 macrophage presence\nC_LIO_LICD8+ T cells are enriched in hypermutated GBMs at diagnosis and recurrence\nC_LI

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Qianghu Wang, Xin Hu, Baoli Hu, Florian Muller, Hoon Kim, Massimo Squatrito, Tom Mikkelsen, Lisa Scarpace, Floris Barthel, Yu-Hsi Lin, Nikunj Satani, Emmanuel Martinez-Ledesma, Edward Chang, Adriana Olar, Guocan Wang, Ana C. deCarvalho, Eskil Eskilsson, Siyuan Zheng, Amy B. Heimberger, Erik P. Sulman, Do-Hyun Nam, Roel G.W. Verhaak. 2016-05-08. Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment. https://doi.org/10.1101/052076

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