AUTHOR'S VIEW OncoImmunology 1:2, 227–228; March/April 2012; G 2012 Landes Bioscience Systemic cancer immunotherapy with Toll-like receptor 7 agonists Timing is everything Christian Hotz1,2 and Carole Bourquin1,2,* 1Center for Integrated Protein Science Munich (CIPSM); Division of Clinical Pharmacology; Department of Internal Medicine; Ludwig-Maximilian University of Munich; Munich, Germany; 2Department of Medicine; University of Fribourg; Fribourg, Switzerland Keywords: TLR7, TLR tolerance, cancer immunotherapy, innate immunity 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 2recept0ors(T1LRs), 2which seLnse aacelnlpopudlation ethat saccumuBlates iin oagonsistR8c48inimeice. Wneshocwed ethat . conserved molecular patterns from micro- cancer patients and suppresses T cell a single injection of R848 blocks the bial pathogens, trigger a cascade of events responses.4 We have elucidated the com- cytokine response to a second stimulation characterized by the secretion of pro- bined molecular basis for these effects by for a time frame beginning 48 h after the inflammatory cytokines that results in the demonstrating that they are mediated by first injection and lasting for up to five stimulation immunity. Agonists of innate of DTLRs and oaretherenfore adaptive oIL-6, proinflammatory tand tydpeI cytokines, iintesrferontsercreteidbbywuithin in particular days. In tthe contrast, efirst .24 repeated h resulted stimulation in an of major interest for the immunotherapy dendritic cells following their activation enhanced response. These findings sug- of cancer. Imiquimod, a small molecule through TLR7.2-4 Thus, TLR7 agonists gested that injections every second to third agonist of TLR7, is already successfully appear to fulfill many of the requirements day, as performed in clinical studies of used for the topical treatment of skin for an effective systemic immunotherapy. TLR7 agonists, would maintain TLR7 in a neoplasias such as basal cell carcinoma.1 In The few studies investigating systemic refractory state. We designed a protocol of view of the potential use of TLR7 ligands application of agonists for TLR7 or its fractionated cancer therapy with R848 in for the treatment of non-skin cancer, we close homolog TLR8 in cancer patients cycles separated by five day intervals to and others have investigated the ability of have however shown little efficacy.5,6 take advantage of the initial receptor prim- TLR7 agonists to induce systemic immune Treatment in these studies consisted of ing and to avoid tolerance. This protocol responses. A combined schematic view of two to three weekly applications. Given blocked tumor growth in a murine cancer the anti-tumor activity of TLR7 agonists the fact that cytokine secretion is crucial model with a higher efficiency than the as demonstrated by our recent work is for the therapeutic effect of TLR7,7 we schedule used in clinical studies, although depicted in Figure 1. We have shown speculated that systemic cancer therapy the cumulated dose was lower.9 that the systemic application of TLR7 with immune response modifiers might be We observed TLR7 tolerance in myeloid ligands functionally activates both CD8+ limited by a phenomenon called TLR dendritic cells, in which the secretion of T cells and NK cells, two major effector tolerance. TLR tolerance is characterized proinflammatory cytokines was inhibited, cell types for anticancer responses.2 by blunted cytokine secretion after repeti- but also in plasmacytoid dendritic cells, Furthermore, TLR7 activation blocks tive receptor stimulation and has been where type I interferon secretion was sup- the suppressive function of regulatory described for several TLRs, including pressed.9 We showed in vivo that tolerance T cells that contribute to cancer-associated TLR7.8 Indeed, we recently demonstrated correlated well with decreasing levels of immune suppression.3 Finally, we have for the first time that TLR tolerance IRAK-1, an essential adaptor molecule for shown that IFN-a produced by plasmacy- influences the efficacy of TLR stimulation type I interferon and cytokine production. toid dendritic cells upon TLR activation for the immunotherapy of cancer.9 In this Furthermore, tolerance was not restricted to reduces the immunosuppressive activity of study we analyzed the kinetics of repeated TLR7: we demonstrated the occurrence of myeloid-derived suppressor cells (MDSC), TLR7 stimulation with the small molecule heterotolerance, since TLR7 stimulation led *Correspondence to: Carole Bourquin; Email: carole.bourquin@unifr.ch Submitted: 09/15/11; Revised: 09/20/11; Accepted: 09/20/11 http://dx.doi.org/10.4161/onci.1.2.18169 www.landesbioscience.com OncoImmunology 227