Cancer Cell. 2017 July 10
Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment
Qianghu Wang,Baoli Hu,Xin Hu,Hoon Kim,Massimo Squatrito,Lisa Scarpace,Ana C. deCarvalho,Sali Lyu,Pengping Li,Yan Li,Floris Barthel,Hee Jin Cho,Yu-Hsi Lin,Nikunj Satani,Emmanuel Martinez-Ledesma,Siyuan Zheng,Edward Chang,Charles-Etienne Gabriel Sauvé,Adriana Olar,Zheng D. Lan,Gaetano Finocchiaro,Joanna J. Phillips,Mitchel S. Berger,Konrad R. Gabrusiewicz,Guocan Wang,Eskil Eskilsson,Jian Hu,Tom Mikkelsen,Ronald A. DePinho,Florian Muller,Amy B. Heimberger,Erik P. Sulman,Do-Hyun Nam,Roel G.W. Verhaak
We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.