Anti-tumor Activity of Toll-Like Receptor 7 Agonists.

Huju Chi,Flora Sha Zhao,Guangyi Jin,Ou Sha,Tzi Bun Ng,Li Zhang,Chunman Li

doi:10.3389/fphar.2017.00304

Abstract

Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

Highlights

Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity (O’Neill et al, 2013)
Gardiquimod has been used in cancer therapy. It exhibited a series of potential benefits in oncotherapy, inhibition of cell proliferation, triggering of apoptosis, and suppression of metastasis etc. (Ma et al, 2010; Weber et al, 2013; Zou et al, 2015). These results suggest that the imidazoquinoline family is promising for application in clinical cancer therapy
Upon administration twice a week, TLR tolerance emerged and no antitumor activity was observed compared with administration once a week, suggesting that activation of DSR-6434 occurs in a dosedependent manner (Nakamura et al, 2013; Adlard et al, 2014; Koga-Yamakawa et al, 2015)

Summary

INTRODUCTION

Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity (O’Neill et al, 2013). TLRs can recognize both pathogen-associated molecular patterns and damage-associated molecular patterns such as lipopolysaccharide and free nucleic acids (Piccinini and Midwood, 2010). Some TLRs are expressed in the intracellular endosomes (TLR3, 7, 8, and 9), while others are localized on the plasmalemma (TLR1, 2, 4, 5, 6, 10, and 11; Hennessy et al, 2010). TLRs are activated by diverse agonists, e.g., TLR4 by lipopolysaccharide, and TLR3, 7 and 9 by nucleic acids (Table 1). Among TLRs, TLR7 is an intracellular receptor expressed on endosomal membranes. TLR7 is closely related to TLR8, which recognizes nucleosides and nucleotides from intracellular pathogens. There are two ligand-binding sites in TLR7. The first site for binding of small ligands is conserved in both TLR7 and TLR8. B16 SK-MEL-13, -28, -37 AGS, BGC-823, MBT-2 AB1 HepG2.2.15 DU145TRAMP-C1, MDA-MB-231, PC3

CpG-ODN IMO 1018 ISS

Findings

CONCLUSION