TLR9 and Glioma: Friends or Foes?

Abstract

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through specific transcription factors. Thus, it has been hypothesized that TLR9 may cause glioma. This article reviews the roles of TLR9 in the pathogenesis of glioma and its related signaling molecules in either defending or promoting glioma. TLR9 mediates the invasion-induced hypoxia of brain cancer cells by the activation of matrix metalloproteinases (2, 9, and 13) in brain tissues. In contrast, the combination of the TLR9 agonist CpG ODN to radiotherapy boosts the role of T cells in antitumor effects. The TLR9 agonist CpG ODN 107 also enhances the radiosensitivity of human glioma U87 cells by blocking tumor angiogenesis. CpG enhances apoptosis in vitro and in vivo. Furthermore, it can enhance the antigen-presenting capacity of microglia, switch immune response toward CD8 T cells, and reduce the number of CD4CD25 Treg cells. CpG ODN shows promise as a potent immunotherapeutic drug against cancer, but specific cautions should be taken when activating TLR9, especially in the case of glioblastoma.

Keywords: TLR9; dichotomic role; glioma; tumor progression; tumor regression.

Figure 1

An overview of TLR9 trafficking and signaling pathway. TLR9s are synthesized in the ER to access the cell surface. They require chaperone molecules UNC93B1 to facilitate loading into COPII vesicles and transport to the Golgi. Then, reaching the Surface TLRs Trafficking to endosomes in DCs depends on AP 2, gp96, Slc15a4, and Slc15a4, accessory proteins needed for TLR9 transport. Upon entry into this compartment, TLR9 is proteolytically cleaved by cathepsins and AEP to generate a mature form. It is in this compartment that signaling leads to activation of the NF-κB pathway through (BAD-LAMP/LAMP5), controlling TLR9 trafficking or AP-3 to type I interferon signaling. The activation of TLR9- IRAK- TRAF signaling pathway triggers in turn the stimulation of transcription factors such as mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and the nuclear factor NF-Κb. TLR9-IRAK1-TRAF3 signaling cascade leads in turn to type I interferon.

Figure 2

Cross-talk between innate and adaptive immune cells. Upon DC stimulation by CpG-DNA, production of TNF-α/β, IL-6, and IL-12, and upregulation CD40, CD70, B7-1 (CD80), B7-2 (CD86), and major (MHC) class II accrue. Upon antigen capture, immature DCs become licensed and activate naïve T cells. DCs are implicated in the cross-presentation of MHC-I molecules. CD4 T-cell engagement induces surface expression of the CD40 ligand, stimulating CD40 signaling in DC. The costimulatory molecule CD70 is also implicated in the priming of CD8 T. NK cells are strongly activated by CpG-ODNs. Depending on the context of Ag presentation, pDCs lead to immunity by stimulating T-cell priming or promoting the induction of T-cell tolerance by inducing regulatory T cells (Tregs), which promotes tumor progression in several solid tumors.

Figure 3

Dichotomic role of TLR9 in Glioma. The role of TLR9 in Glioma on one hand could have an antitumor effect. In fact, TLR9 agonists induce inhibition of angiogenesis by inhibition of VEGF and HIF secretion, inducing G1 arrest of the cell cycle through NF-κB pathway. On the other hand, TLR9 has a dark side, leading to tumor progression mediated through the activation of the JAK2 and STAT3 transcription factor TLR9 mediate CpG oligonucleotide-induced cellular invasion by increasing the matrix metalloproteinase MMP2, 9, and 13 levels through hypoxia.