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

K Dziurzynski, J Wei, W Qiao, MA Hatiboglu… - Clinical Cancer …, 2011 - AACR
K Dziurzynski, J Wei, W Qiao, MA Hatiboglu, LY Kong, A Wu, Y Wang, D Cahill, N Levine…
Clinical Cancer Research, 2011AACR
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 …
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. Clin Cancer Res; 17(14); 4642–9. ©2011 AACR.
AACR