Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers

Figure 4

TLR signalling transducing pathways and the related immunotherapy approaches. Toll-like receptors are expressed in both immune and tumor cells, making difficult to decipher their function in cancer. Thus, their modulation in tumor microenvironment results from a complex balance of host and infected/tumor cell mechanisms which affects their expression and activation. They are activated by specific ligands (for each TLR) and synthetic substances as showed in the figure: (1) single-stranded RNA and imiquimod for TLR7, (2) double-stranded RNA and poly(I:C) for TLR3, (3) ssRNA and VTX-2337 for TLR8, (4) LPS, lipoteichoic acid, and Picibanil for TLR4, (5) lipoproteins, peptidoglycans, lipoteichoic acids, zymosan, mannan, tGPI-mucin, and ISA201 for TLR2, (6) unmethylated dinucleotide cytosine-guanine and EMD 1201081 for TLR9, and (7) flagellin and CBLB502 for TLR5. Once activated, the signal transduction depends on adapter molecules such as MyD88, TIRAP, TRIF, and TRAM in order to activate the transcription of type I interferons and TLR-induced genes. All TLRs, except TLR3, require MyD88 for propagation of their signals. TLR4 requires myeloid differentiation factor-2 (MD-2) as a coactivator for its activation by LPS binding [3, 5]. TIRAP: TIR-domain-containing adaptor protein; MyD88: myeloid differentiation primary response protein 88; IRAK: IL-1R-associated kinase; TRAM: Toll receptor-associated molecule; TRIF: TIR-domain-containing adapter-inducing interferon-β; TRAF: TNF receptor-associated factor; RIP-1: receptor-interacting protein kinase-1; TAK: TNF receptor-associated factor; TAB: TGF-β-activated kinase I/MAP3K7-binding protein; IKK: inhibitor of kappa B kinase; IκBα: nuclear factor of kappa B, alpha; IRF: interferon regulatory factor; U: ubiquitination; P: phosphorylation.