title: Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses.
abstract: Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly(I:C) that mimics virally induced immune activation. Timing of the stimulations was important, as sequential stimulation with poly(I:C) and the TLR7 agonist R848 interspaced by 24 h induced higher MAPK and NFkB signaling in DC than the simultaneous application of the same ligands. DC activated by sequential poly(I:C)/R848 stimulation efficiently induced Th1 differentiation and primed NK-cell and cytotoxic T-cell responses. We have developed a treatment regimen taking advantage of TLR7 reprogram-ming that cured over 80% of large immunogenic tumors in mice by the action of NK cells and cytotoxic T cells. These results have direct implications for the use of these clinically established ligands in the immunotherapy of cancer.
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Hotz
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Treinies
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland; Section of Pharmaceutical Sciences, Faculty of Science, and Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Ines
authors.initials: I
authors.lastname: Mottas
authors.affiliation: Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich , Munich, Germany.
authors.forename: Laurin C
authors.initials: LC
authors.lastname: Rötzer
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Oberson
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spagnuolo
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Perdicchio
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Spinetti
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Herbst
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland; Section of Pharmaceutical Sciences, Faculty of Science, and Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Bourquin
keywords: Cancer immunotherapy; RIG-I-like receptors agonists; Toll-like receptors; dendritic cells; poly(I:C)