Figure 1. Overview of the cellular mechanisms of TLR7-targeting therapy. DC: dendritic cell, Teff: effector T cells, Treg: regulatory T cell, MDSC: myeloid- of © derived suppressor 2012 cell, NK: natural killer cell, Landes ssRNA: single-stranded RNA. Bioscience. to blunted cytokine secretion by subsequent tolerance,9 IL-10 may also limit the concomitantly. The application of a frac- TLR2, 4 and 9 stimulation. Given the efficiency immunotherapy. It was tionated schedule to prevent tolerance global occurrence of tolerance, our results recently demonstrated that IL-10 sup- in protocols employing combinatorial may impact all therapeutic approaches presses proinflammatory cytokine secre- stimulation may therefore prove beneficial dendritic TLR7 Do not distribute. relying on repetitive stimulation with tion following simultaneous stimulation by both enhancing the secretion of proin- immune response modifiers. of two independent TLR pathways, thus flammatory cytokines and preventing high Interestingly, in contrast to the secre- reducing the number of tumor-specific production of IL-10. In conclusion, we tion block observed for proinflammatory CD8+ T cells and impairing the efficiency suggest that a careful evaluation of the cytokines, secretion of the suppressive of cancer immunotherapy.10 It is probable timing of TLR stimulation and the profile cytokine IL-10 was enhanced in tolerized that during simultaneous stimulation of cytokines induced essential for cells. Although not causally two independent pathways, both effective systemic immunotherapy with involved in induction are affected by induction TLR agonists. tolerance of is the of References 1. Peris K, Campione E, Micantonio T, Marulli GC, Fargnoli MC, Chimenti S. Imiquimod treatment of superficial and nodular basal cell carcinoma: 12-week open-label trial. Dermatol Surg 2005; 31:318-23; PMID:15841634; http://dx.doi.org/10.1111/j.1524- 4725.2005.31081 2. Bourquin C, Schmidt L, Lanz AL, Storch B, Wurzenberger C, Anz D, et al. Immunostimulatory RNA oligonucleotides induce an effective antitumoral NK cell response through the TLR7. J Immunol 2009; 183:6078-86; PMID:19890064; http://dx.doi.org/10. 4049/jimmunol.0901594 3. Anz D, Koelzer VH, Moder S, Thaler R, Schwerd T, Lahl K, et al. Immunostimulatory RNA blocks suppression by regulatory T cells. J Immunol 2010; 184:939-46; PMID:19966212; http://dx.doi. org/10.4049/jimmunol.0901245 4. Zoglmeier C, Bauer H, Norenberg D, Wedekind G, Bittner P, Sandholzer N, et al. CpG blocks immuno- suppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res 2011; 17:1765- 75; PMID:21233400; http://dx.doi.org/10.1158/1078- 0432.CCR-10-2672 228 OncoImmunology Volume 1 Issue 2 TLR 5. Dummer R, Hauschild A, Becker JC, Grob JJ, Schadendorf D, Tebbs V, et al. An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin Cancer Res 2008; 14:856-64; PMID:18245549; http://dx.doi.org/10.1158/1078- 0432.CCR-07-1938 6. Geller MA, Cooley S, Argenta PA, Downs LS, Carson LF, Judson PL, et al. Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers. Cancer Immunol Immunother 2010; 59:1877-84; PMID:20820775; http://dx.doi. org/10.1007/s00262-010-0914-1 7. Rajagopal D, Paturel C, Morel Y, Uematsu S, Akira S, Diebold SS. Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists. Blood 2010; 115:1949-57; PMID: 20065291; http://dx.doi.org/10.1182/blood-2009-08- 238543 8. Broad A, Kirby JA, Jones DE. Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon- beta production. Immunology 2007; 120:103-11; PMID:17034424; http://dx.doi.org/10.1111/j.1365- 2567.2006.02485.x 9. Bourquin C, Hotz C, Noerenberg D, Voelkl A, Heidegger S, Roetzer LC, et al. Systemic Cancer Therapy with a Small Molecule Agonist of Toll-like Receptor 7 Can Be Improved by Circumventing TLR Tolerance. Cancer Res 2011; 71:5123-33; PMID: 21697281; http://dx.doi.org/10.1158/0008-5472.CAN- 10-3903 10. Bogunovic D, Manches O, Godefroy E, Yewdall A, Gallois A, Salazar AM, et al. TLR4 Engagement during TLR3-Induced Proinflammatory Signaling in Dendritic Cells Promotes IL-10-Mediated Suppres- sion of Antitumor Immunity. Cancer Res 2011; 71:5467-76; PMID:21730023; http://dx.doi.org/10. 1158/0008-5472.CAN-10-3988