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

Abstract

Smoldering inflammation often increases the risk of progression for malignant tumors and simultaneously matures myeloid dendritic cells (mDCs) for cell-mediated immunity. PolyI:C, a dsRNA analog, is reported to induce inflammation and potent antitumor immune responses via the Toll-like receptor 3/Toll-IL-1 receptor domain-containing adaptor molecule 1 (TICAM-1) and melanoma differentiation-associated protein 5/IFN-β promoter stimulator 1 (IPS-1) pathways in mDCs to drive activation of natural killer cells and cytotoxic T lymphocytes. Here, we found that i.p. or s.c. injection of polyI:C to Lewis lung carcinoma tumor-implant mice resulted in tumor regression by converting tumor-supporting macrophages (Mfs) to tumor suppressors. F4/80(+)/Gr1(-) Mfs infiltrating the tumor respond to polyI:C to rapidly produce inflammatory cytokines and thereafter accelerate M1 polarization. TNF-α was increased within 1 h 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(+) Mfs in tumors extracted from polyI:C-injected mice sustained Lewis lung carcinoma 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 Mfs. These responses were completely abrogated in TICAM-1(-/-) mice, and unaffected in myeloid differentiation factor 88(-/-) and IPS-1(-/-) mice. Thus, the TICAM-1 pathway is not only important to mature mDCs for cross-priming and natural killer cell activation in the induction of tumor immunity, but also critically engaged in tumor suppression by converting tumor-supporting Mfs to those with tumoricidal properties.

• Authors: Hiroaki Shime, Misako Matsumoto, Hiroyuki Oshiumi, Shinya Tanaka, Akio Nakane, Yoichiro Iwakura, Hideaki Tahara, Norimitsu Inoue, Tsukasa Seya
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 6 Pg. 2066-71 (Feb 07 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22308357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport
• Antineoplastic Agents
• IPS-1 protein, mouse
• TICAM-1 protein, mouse
• Toll-Like Receptor 3
• Tumor Necrosis Factor-alpha
• Poly I-C

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adaptor Proteins, Vesicular Transport (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Lewis Lung (immunology, pathology)
• Cell Polarity (drug effects, immunology)
• Cytotoxicity, Immunologic (drug effects)
• Macrophages (drug effects, immunology, pathology)
• Mice
• Myeloid Cells (immunology, pathology)
• Poly I-C (pharmacology)
• Signal Transduction (drug effects, immunology)
• Toll-Like Receptor 3 (immunology)
• Tumor Necrosis Factor-alpha (metabolism)