Synergistic toll-like receptor 3/9 signaling affects properties and impairs glioma-promoting activity of microglia


  • Y. Huang
  • Q. Zhang
  • M. Lubas
  • Y. Yuan
  • F. Yalcin
  • I.E. Efe
  • P. Xia
  • E. Motta
  • A. Buonfiglioli
  • S. Lehnardt
  • O. Dzaye
  • C. Flueh
  • M. Synowitz
  • Feng Hu
  • H. Kettenmann


  • Journal of Neuroscience


  • J Neurosci 40 (33): 6428-6443


  • In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon β release and phagocytic tumor clearance. Combined TLR3/9 stimulation also augmented several functional features of microglia such as the release of pro-inflammatory factors, motility and phagocytosis activity. TLR3/9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the co-activation of TLR3/9 also augments the impairment of glioma growth in vivo. Our results show that combined activation of TLR3/9 in microglia/macrophages results in a more efficient glioma suppression, which may provide a potential strategy for glioma treatment. SIGNIFICANCE STATEMENT: GAMs (Glioma associated microglia/macrophages) are the predominant immune cells in glioma growth and are recently considered as anti-tumor targets. TLRs are involved in glioma growth, but the TLR3 or TLR9 ligands were not successful in clinical trials in treating glioma. We therefore combined TLR3 and TLR9 activation of GAMs resulting in a strong synergistic effect of tumor clearance in vitro, ex vivo and in vivo. Mechanisms of this GAM-glioma interaction involve IFNß signaling and increased tumor clearance by GAMs. Interfering with CD47 signaling had an additional impact on tumor clearance. We propose that these signaling pathways could be exploited as anti-glioma targets.