Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Hotz, Christian; Treinies, Marina; Mottas, Inès; Rötzer, Laurin C.; Oberson, Anne; Spagnuolo, Lorenzo; Perdicchio, Maurizio; Spinetti, Thibaud; Herbst, Tina; Bourquin, Carole

doi:10.1080/2162402X.2016.1232219

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Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses

Hotz, Christian Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Treinies, Marina Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Mottas, Inès Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland - Section of Pharmaceutical Sciences, Faculty of Science, and Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Switzerland
Rötzer, Laurin C. Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, Germany
Oberson, Anne Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Spagnuolo, Lorenzo Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Perdicchio, Maurizio Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Spinetti, Thibaud Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Herbst, Tina Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland
Bourquin, Carole Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Switzerland - Section of Pharmaceutical Sciences, Faculty of Science, and Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Switzerland

01.11.2016

Published in:

OncoImmunology. - 2016, vol. 5, no. 11, p. e1232219

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Médecine

Language

English

Classification

Biological sciences

License

License undefined

Identifiers

RERO DOC 278635
DOI 10.1080/2162402X.2016.1232219

Persistent URL

https://folia.unifr.ch/unifr/documents/305438

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