The application of Toll like receptors for cancer therapy

Abstract

Toll-like receptor (TLR) proteins play key roles in immune responses against infection. Using TLR proteins, host can recognize the conserved molecular structures found in pathogens called pathogen-associated molecular patterns (PAMPs). At the same time, some TLRs are able to detect specific host molecules, such as high-mobility group box protein 1 (HMGB1) and heat shock proteins (hsp), and lead to inflammatory responses. Thus, it has been suggested that TLRs are involved in the development of many pathogenic conditions. Recent advances in TLR-related research not only provide us with scientific information, but also show the therapeutic potential against diseases, such as autoimmune disease and cancer. In this mini review, we demonstrate how TLRs pathways could be involved in cancer development and their therapeutic application, and discuss recent patentable subjects, in particular, that are targeting this unique pathway.

Keywords: HPV; TLR; bladder cancer; breast cancer; carcinoma; colon cancer; skin tumor; vaccination.

Fig 1

Diagram of TLR signaling pathways. TLRs localize to different subcellular compartments according to the molecular nature of the relevant ligands. TLR3, TLR7/8 and TLR9 are located at endolysosomal compartment and recognized dsRNA or ssRNA or unmethylated CpG DNA, respectively. In contrast, TLR2, TLR4, TLR5, and TLR11 are mainly displayed on plasma membrane and recognize indicated ligands. TLR2/1 heterodimers respond to triacyl lipopeptide, while TLR2/6 heterodimers recognize diacyl lipopeptide. CD14 and MD-2 are accessory proteins required for LPS/TLR4 ligation. Following ligation with their respective ligands, TLRs recruit downstream adaptor molecules, such as MyD88 (all TLRs except TLR3) and TRIF (TLR3 and TLR4), to activate IRAK4, TRAF6 and IKKε/TBK1. These sequentially activate signaling pathway of NF-κB, p38 MAPK and JNK, leading to a series of specific cellular responses related to cell survival, proliferation and inflammation. IRF3 and 7 are also activated downstream of TLR3, 7, 8 and 9. These signaling mediate the production of type 1 interferon and antiviral immune responses. MyD88:Myeloid differentiation primary-response protein 88, IRAK:IL-1R-associated kinase, TRAM:TRIF-related adaptor molecules, TIRAP:TIR domain containing adaptor protein, TRAF:TNF receptor-associated factor, TAB:TGF-β activated kinase 1/MAP3K7 binding protein, TAK:TGF--activated kinase,IKK:inhibitor of kappa light polypeptide gene enhancer in B-cells kinase, MIKK:mitogen-activated protein kinase kinase.