TLR7 and TLR8 as targets in cancer therapy.
Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/8-mediated activation of the central transcription factor nuclear factor-kappaB, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2- and caspase-dependent proapoptotic activity against tumor cells.
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Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany. michael.schoen@virchow.uni-wuerzburg.de
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D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D000077271:Imiquimod; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000970:Antineoplastic Agents; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D000077271:Imiquimod