TLR7 and TLR8 as targets in cancer therapy

Abstract

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-jB, 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.

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

“…Preclinical studies were followed by extensive testing of imiquimod in clinical trials for the treatment of cutaneous tumors. Clinical responsiveness to topical treatment with imiquimod (Aldara 5% cream) was found to be effective for both primary skin tumors and cutaneous metastases, as reviewed by Schön and Schön [111]. In these reports, no TAAs were added, and the immuneenhancing effects of imiquimod were sufficient to elicit an antitumor response.…”

TRAIL+ Human Plasmacytoid Dendritic Cells Kill Tumor Cells In Vitro: Mechanisms of Imiquimod- and IFN-α–Mediated Antitumor Reactivity

“…Firstly, IMQ when applied topically or injected into the tissue stimulates the release of proinflammatory cytokines and chemoattractants (Fig. 3A) (13). DCs represent a major portion of such an IMQinduced infiltrate (14,15,21).…”

“…In addition to their role in viral immunity, several studies propose a direct role for cytotoxic pDCs in antitumor immunity. The synthetic TLR7/8 agonist imiquimod (IMQ) is a highly effective topical treatment for epithelial skin tumors such as basal cell carcinomas, viral acanthomas, and even melanomas (13). Regressing cancers were surrounded and heavily infiltrated by inflammatory-type DCs (14,15), some of which expressed lytic molecules (15).…”

Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma

“…Currently, imiquimod (Aldara 5% cream, 3M) is the only TLR7/8 agonist to receive FDA approval and is licensed in oncology for the topical treatment of basal cell carcinoma and other dermatologic malignancies. 16 With the exception of therapeutic vaccination approaches, topical administration of TLR agonists is of limited utility in the treatment of the majority of solid tumors and in settings of nondermatologic disseminated disease.…”