Deciphering glioma intrinsic transcriptional subtypes identifies tumor evolution associates with changes in immune-microenvironment
Wang QH, Hu BL, Hu X, Squatrito M, Scarpace L, Decarvalho AC, Lyu S, Li PP, Li Y, Barthel FP, Cho HJ, Lin YH, Satani N, Martinez-Ledesma E, Zheng SY, Chang E, Olar A, Lan ZD, Finocchiaro G, Phillips JJ, Berger MS, Gabrusiewicz K, Wang GC, Eskilsson E, Hu J, Mikkelsen T, Depinho R, Muller F, Heimberger A, Sulman E, Nam DH, and Verhaak R. Deciphering glioma intrinsic transcriptional subtypes identifies tumor evolution associates with changes in immune-microenvironment. Neuro-Oncology 2017; 19(suppl 6):vi247-vi248.
Glioblastoma expression subtypes have been previously been associated with genomic abnormalities, treatment response, and differences in tumor microenvironment. 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, a revision of the previously reported TCGA subtypes. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and the 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. Comparison of matching primary and recurrent gliomas elucidated treatment-induced phenotypic tumor evolution, including expression subtype switching, in 45% of our cohort as well as associations between microenvironmental components and treatment response. 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 was associated with CD8+ T cell enrichment. Frequency of M2 macrophage detection was associated with short-term relapse after radiation therapy. Our study provides a comprehensive transcriptional and cellular landscape of IDH wild-type glioblastoma during treatment modulated tumor evolution. Characterization of the evolving glioblastoma transcriptome and tumor microenvironment aids in designing more effective immunotherapy trials.