Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype

Kristine Dziurzynski, Jun Wei, Wei Qiao, Mustafa Aziz Hatiboglu, Ling Yuan Kong, Adam Wu, Yongtao Wang, Daniel Cahill, Nicholas Levine, Sujit Prabhu, Ganesh Rao, Raymond Sawaya, Amy B. Heimberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Purpose: Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited. Experimental Design: Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The glioma cancer stem cell (gCSC) CMV interleukin (IL)-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF (vascular endothelial growth factor), TGF-β, viral IE1, and pp65 were determined by flow cytometry. The influence of CMV IL-10 - treated monocytes on gCSC biology was ascertained by functional assays. Results: CMV showed a tropism for macrophages (MΦ)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the central nervous system MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by downmodulation of the major histocompatibility complex and costimulatory molecules) while upregulating immunoinhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10 - treated monocytes produced angiogenic VEGF, immunosuppressive TGF-β, and enhanced migration of gCSCs. Conclusions: CMV triggers a feedforward mechanism of gliomagenesis by inducing tumor-supportive monocytes.

Original languageEnglish (US)
Pages (from-to)4642-4649
Number of pages8
JournalClinical Cancer Research
Volume17
Issue number14
DOIs
StatePublished - Jul 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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