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Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors

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Title: Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors
Authors: Shime, Hiroaki Browse this author →KAKEN DB
Matsumoto, Misako Browse this author →KAKEN DB
Oshiumi, Hiroyuki Browse this author →KAKEN DB
Tanaka, Shinya Browse this author →KAKEN DB
Nakane, Akio Browse this author
Iwakura, Yoichiro Browse this author
Tahara, Hideaki Browse this author
Inoue, Norimitsu Browse this author
Seya, Tsukasa Browse this author →KAKEN DB
Keywords: Toll-like receptor
tumor-associated macrophages
Issue Date: 7-Feb-2012
Publisher: National Academy of Sciences
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 109
Issue: 6
Start Page: 2066
End Page: 2071
Publisher DOI: 10.1073/pnas.1113099109
Abstract: Smoldering inflammation often increases the risk of progression for malignant tumors and simultaneously matures myeloid dendritic cells (mDC) for cell-mediated immunity. PolyI:C, a dsRNA analog, is reported to induce inflammation and potent antitumor immune responses via the TLR3/TICAM-1 and MDA5/IPS-1 pathways in mDC to drive activation of NK cells and cytotoxic T lymphocytes. Here, we found that intraperitoneal or subcutaneous injection of polyI:C to 3LL tumor-implant mice resulted in tumor regression by converting tumor-supporting macrophages (Mf) to tumor suppressors. F4/80+/Gr1- Mf infiltrating the tumor respond to polyI:C to rapidly produce inflammatory cytokines and thereafter accelerate M1 polarization. TNF-α was increased within 1 hour in both tumor and serum upon polyI:C injection into tumor-bearing mice followed by tumor hemorrhagic necrosis and growth suppression. These tumor responses were abolished in TNF-α-/- mice. Furthermore, F4/80+ Mf in tumors extracted from polyI:C-injected mice sustained 3LL cytotoxic activity, and this activity was partly abrogated by anti-TNF-α Ab. Genes for supporting M1 polarization were subsequently up-regulated in the tumor-infiltrating Mf. These responses were completely abrogated in TICAM-1-/- mice, and unaffected in MyD88-/- and IPS-1-/- mice. Thus, the TICAM-1 pathway is not only important to mature mDC for cross-priming and NK cell activation in the induction of tumor immunity, but also critically engaged in tumor suppression by converting tumor-supporting Mf to those with tumoricidal properties.
Type: article (author version)
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 瀬谷 司

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