Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype
Konrad Gabrusiewicz, … , Erik P. Sulman, Amy B. Heimberger
Konrad Gabrusiewicz, … , Erik P. Sulman, Amy B. Heimberger
Published February 25, 2016
Citation Information: JCI Insight. 2016;1(2):e85841. https://doi.org/10.1172/jci.insight.85841.
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Research Article Cell biology Immunology

Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype

Abstract

Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages.

Authors

Konrad Gabrusiewicz, Benjamin Rodriguez, Jun Wei, Yuuri Hashimoto, Luke M. Healy, Sourindra N. Maiti, Ginu Thomas, Shouhao Zhou, Qianghu Wang, Ahmed Elakkad, Brandon D. Liebelt, Nasser K. Yaghi, Ravesanker Ezhilarasan, Neal Huang, Jeffrey S. Weinberg, Sujit S. Prabhu, Ganesh Rao, Raymond Sawaya, Lauren A. Langford, Janet M. Bruner, Gregory N. Fuller, Amit Bar-Or, Wei Li, Rivka R. Colen, Michael A. Curran, Krishna P. Bhat, Jack P. Antel, Laurence J. Cooper, Erik P. Sulman, Amy B. Heimberger

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Figure 1

Peripheral monocyte lineage dysregulation in glioblastoma patients.

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Peripheral monocyte lineage dysregulation in glioblastoma patients. Numb...
Numbers of (A) monocytes and (B) myeloid-derived suppressor cells (MDSCs) in blood samples obtained from healthy donors (red circles, n = 57), low-grade (I + II) brain tumor patients (black squares, n = 33), grade III brain tumor patients (blue triangles, n = 30), and glioblastoma (GBM) patients (green triangles, n = 60) were measured using an XN-10 automated analyzer. The data are presented as the mean ± SD. An unpaired t test with Welch’s correction was used to calculate P values. ***P < 0.001; ****P < 0.0001. (C) Gene expression profiles of CD14+ blood cells isolated from GBM patients (n = 4) and healthy blood donors (n = 4), as determined using a microarray. A heat map of 764 differentially expressed genes (472 upregulated and 292 downregulated) is shown. (D) Hallmark biological states or processes enriched in GBM patient CD14+ blood cells relative to healthy donors according to gene set enrichment analysis. The normalized enrichment score, enrichment signal of leading edge gene subset (signal), and false discovery rate (FDR) q values are shown. (E) Canonical pathway activity was predicted using ingenuity pathway analysis. The activation z-score, fraction of genes affected in each pathway, and Fisher’s exact test overlap log-transformed P values are presented. (F) Nanostring digital gene expression profiling of 99 immune system– and cancer-related genes and 5 lncRNAs in GBM CD14+ blood cells (n = 11) and phenotypically matched healthy donor cells (n = 11). A heat map of 41 differentially expressed genes (25 upregulated and 16 downregulated) is shown. An asterisk indicates a GBM blood CD14+ sample clustered with samples obtained from healthy donors.