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

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.