Sponsored by
Clin Cancer Res. 2011 Apr 13. [Epub ahead of print]
Dziurzynski K, Wei J, Qiao W, Hatiboglu MA, Kong LY, Wu A, Wang Y, Cahill D, Levine NB, Prabhu S, Rao G, Sawaya R, Heimberger AB.
Neurosurgery, UTMDACC.
Abstract
PURPOSE: 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 gCSC CMV IL-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF, TGF-beta, 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 demonstrated a tropism for macrophages (M Phi s)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the CNS M Phi s/microglia) to assume an M2 immunosuppressive phenotype (as manifested by down modulation of the major histocompatibility complex and costimulatory molecules) while up regulating immune inhibitory 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 angiogeneic VEGF, immunosuppressive TGF-beta, and enhanced migration of gCSCs.
CONCLUSIONS: CMV triggers a feed-forward mechanism of gliomagenesis by inducing tumor-supportive monocytes.