The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

Methods

Referenced papers were identified using multiple electronic searches of the Medline database with the keywords (alone or in combination): toll-like receptors (TLRs), cancer, TLR ligands, NF-κB, innate immunity, acquired immunity and immunotherapy. The search strategy incorporated MESH terms, and results were evaluated for sensitivity and specificity. Additional articles were identified from the references of retrieved papers. Papers were included on the basis of evidence supporting individual points.

Background

A total of 13 mammalian toll paralogues (11 of which are expressed in humans) termed TLR have been described (O'Neill, 2006). Toll-like receptors expressed on immune system sentinel cells such as dendritic cells and macrophages sense a range of chemicals produced by bacteria, viruses, fungi and protozoa. For example lipid-based predominantly bacterial structures such as mycobacterial lipopeptides and lipopolysaccaride are recognised by TLR2 (in combination with TLR1 or TLR6 as heterodimers) and TLR4 (as a homodimer), respectively, while viral and/or bacterial nucleic acids are recognised by TLR3 (stranded RNA (dsRNA)), TLR7, TLR8 and TLR9 (CpG motifs in DNA). Toll-like receptors are also extensively expressed on other cell types and may have endogenous ligands (Cook et al, 2004).