Toll-like Receptor 2 Activation Promotes Tumor Dendritic Cell Dysfunction by Regulating IL-6 and IL-10 Receptor Signaling.

Abstract

Although dendritic cell (DC) dysfunction in cancer is a well-recognized consequence of cancer-associated inflammation that contributes to immune evasion, the mechanisms that drive this process remain elusive. Here, we show the critical importance of tumor-derived TLR2 ligands in the generation of immunosuppressive IL-10-producing human and mouse DCs. TLR2 ligation induced two parallel synergistic processes that converged to activate STAT3: stimulation of autocrine IL-6 and IL-10 and upregulation of their respective cell surface receptors, which lowered the STAT3 activation threshold. We identified versican as a soluble tumor-derived factor that activates TLR2 in DCs. TLR2 blockade in vivo improved intra-tumor DC immunogenicity and enhanced the efficacy of immunotherapy. Our findings provide a basis for understanding the molecular mechanisms of DC dysfunction in cancer and identify TLR2 as a relevant therapeutic target to improve cancer immunotherapy.

• Authors: Michael Tang, Jun Diao, Hongtao Gu, Ismat Khatri, Jun Zhao, Mark S Cattral
• Journal: Cell reports (Cell Rep) Vol. 13 Issue 12 Pg. 2851-64 (Dec 29 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26711349 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• IL10 protein, human
• Interleukin-6
• Toll-Like Receptor 2
• Interleukin-10

Topics

• Animals
• Cell Line, Tumor
• Dendritic Cells (immunology)
• Humans
• Immunotherapy (methods)
• Interleukin-10 (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Male
• Melanoma, Experimental (immunology, metabolism, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasms (immunology, metabolism, therapy)
• Signal Transduction
• Toll-Like Receptor 2 (immunology, metabolism)