Heterogeneity of Toll-like receptor 9 signaling in B cell malignancies and its potential therapeutic application

Abstract

Toll-like receptor 9 (TLR9) is expressed in a variety of B-cell malignancies and works as a bridge between innate and adaptive immunity. CpG oligodeoxynucleotides (CpG ODNs), TLR9 agonists, are able to induce anticancer immune responses and exert direct effects against cancer cells, serving as cancer therapeutic agents. Therefore, TLR9 might be a potential therapeutic target for drug development. However, several new evidences have revealed that direct effects of TLR9 agonists on B-cell malignancies is controversial. For example, CpG ODNs can induce apoptosis in certain type of chronic lymphocytic leukemia and lymphoma cells, while induce proliferation in multiple myeloma and other types of lymphoma cells. In this review, we summarize current understanding of the heterogeneity in responses of normal and malignant B cells to TLR9 agonists, due to differences in TLR9 expression levels, genetic alterations (such as MyD88 mutation), and signaling pathway activation. Especially, the downstream molecules of NF-κB signaling pathway play an important role in the heterogeneous response. In order to provide possibilities for therapeutic manipulation of TLR9 agonists in the treatment of these disorders, the preclinical and clinical advances in using CpG ODNs alone and in combination therapies are also summarized in this review.

Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling

“…S7A and S7B). These results paralleled the response for the activation of TLR9-dependent pathways (33,34). NETs significantly enhanced TLR9 expression together with an increase in the phosphorylation of NFkB, MAPK/p38, and STAT3 in SU-DHL2 cells (Fig.…”

“…TLR9 was mainly expressed in immune cells including B cells, dendritic cells, and macrophages, and it acts as a bridge between innate and adaptive immunity in the antitumor responses in solid tumors (38). But in DLBCL, tumor cells can express TLR9 and directly response to the activation of TLR9 (32), and increasing evidence has shown that TLR9 expression on DLBCL exhibits high heterogeneity and the activation of TLR9 in normal or tumor B cells elicits the opposite biological effects (34). James and colleagues found that inhibiting TLR9 in normal B cells could increase accumulation of MYD88 L265P plasmablasts and may impair B-cell malignancies treatment (39).…”

Development of DNA tetrahedron-based drug delivery system

“…Unmethylated cytosine-guanine dinucleotide-containing oligodeoxynucleotide, as an agonist of Toll-like receptor 9 (TLR9), activates immune responses for use as vaccines to treat cancer, infectious diseases, and allergies (Bai et al., 2017 ). The obstacles in clinical application of CpG are the degradation by DNase in physiological conditions and low uptake efficiency by cells.…”

CpG Oligodeoxynucleotide Developed to Activate Primate Immune Responses Promotes Antitumoral Effects in Combination with a Neoantigen-Based mRNA Cancer Vaccine

“…These results may support the hypothesis that CpG stimulates TLR9 expression in CD19-positive B cells and thus leads to systemic antitumor adaptive immunity. 25 …”