Journal
ONCOIMMUNOLOGY
Volume 5, Issue 11, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2016.1232219
Keywords
Cancer immunotherapy; dendritic cells; poly(I:C); RIG-I-like receptors agonists; Toll-like receptors
Categories
Funding
- Swiss Cancer League Grant [KLS-2910-02-2012]
- Swiss National Science Foundation [31003A_138284, 310030-156372, PDFMP3_137079]
- National Center of Competence in Research Bio-Inspired Materials
- Swiss National Science Foundation (SNF) [310030_156372, PDFMP3_137079, 31003A_138284] Funding Source: Swiss National Science Foundation (SNF)
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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 TLR7dependent 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 reprogramming 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.
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