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

doi:10.1016/j.ccell.2017.06.003

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

Cancer Cell. 2017 Jul 10;32(1):42-56.e6. doi: 10.1016/j.ccell.2017.06.003.

Authors

Qianghu Wang¹, Baoli Hu², Xin Hu³, Hoon Kim⁴, Massimo Squatrito⁵, Lisa Scarpace⁶, Ana C deCarvalho⁶, Sali Lyu⁷, Pengping Li⁷, Yan Li⁷, Floris Barthel⁴, Hee Jin Cho⁸, Yu-Hsi Lin⁹, Nikunj Satani⁹, Emmanuel Martinez-Ledesma¹⁰, Siyuan Zheng¹⁰, Edward Chang¹⁰, Charles-Etienne Gabriel Sauvé², Adriana Olar¹¹, Zheng D Lan², Gaetano Finocchiaro¹², Joanna J Phillips¹³, Mitchel S Berger¹³, Konrad R Gabrusiewicz¹⁴, Guocan Wang², Eskil Eskilsson¹⁰, Jian Hu², Tom Mikkelsen¹⁵, Ronald A DePinho², Florian Muller¹⁶, Amy B Heimberger¹⁴, Erik P Sulman¹⁷, Do-Hyun Nam¹⁸, Roel G W Verhaak¹⁹

Affiliations

¹ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Texas-Houston Graduate School in Biomedical Sciences, Houston, TX 77030, USA.
⁴ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁵ Cancer Cell Biology Programme, Seve Ballesteros Foundation Brain Tumor Group, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain.
⁶ Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
⁷ Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China; Collaborative Innovation Center for Cardiovascular Disease, Nanjing Medical University, Nanjing 211166, China.
⁸ Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea.
⁹ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Departments of Pathology and Laboratory Medicine, Neurosurgery Medical University of South Carolina, and Hollings Cancer Center, Charleston, SC 29425, USA.
¹² Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milano, Italy.
¹³ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁴ Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁵ Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
¹⁶ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁷ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: epsulman@mdanderson.org.
¹⁸ Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea; Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea. Electronic address: nsnam@skku.edu.
¹⁹ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. Electronic address: roel.verhaak@jax.org.

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.

Keywords: disease recurrence; glioblastoma; immune cells; macrophages/microglia; mesenchymal subtype; proneural to mesenchymal transition; tumor evolution; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Glioblastoma / genetics*
Glioblastoma / immunology
Glioblastoma / pathology
Humans
Phenotype
Recurrence
Survival Analysis
T-Lymphocytes / immunology
Tumor Microenvironment / immunology*

Abstract

Publication types

MeSH terms

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