Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2017 Jul 12

PMID 28697342

Citations 966

Authors

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 Sauve

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

Affiliations

Soon will be listed here.

Abstract

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.

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