Do not distribute. Systemic cancer immunotherapy with Toll-like receptor 7 agonists Timing is everything

Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. Toll-like receptors (TLRs), which sense conserved molecular patterns from micro-bial pathogens, trigger a cascade of events characterized by the secretion of pro-inflammatory cytokines that results in the stimulation of innate and adaptive immunity. Agonists of TLRs are therefore of major interest for the immunotherapy of cancer. Imiquimod, a small molecule agonist of TLR7, is already successfully used for the topical treatment of skin neoplasias such as basal cell carcinoma.1 In view of the potential use of TLR7 ligands for the treatment of non-skin cancer, we and others have investigated the ability of TLR7 agonists to induce systemic immune responses. A combined schematic view of the anti-tumor activity of TLR7 agonists as demonstrated by our recent work is depicted in Figure 1. We have shown that the systemic application of TLR7 ligands functionally activates both CD8+ T cells and NK cells, two major effector cell types for anticancer responses.2 Furthermore, TLR7 activation blocks the suppressive function of regulatory T cells that contribute to cancer-associated immune suppression.3 Finally, we have shown that IFN-a produced by plasmacy-toid dendritic cells upon TLR activation reduces the immunosuppressive activity of myeloid-derived suppressor cells (MDSC), a cell population that accumulates in cancer patients and suppresses T cell responses.4 We have elucidated the com-bined molecular basis for these effects by demonstrating that they are mediated by proinflammatory cytokines, in particular IL-6, and type I interferon secreted by dendritic cells following their activatio