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Toll-like receptor 3 signal augments radiation-induced tumor growth retardation in a murine model

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/70877

Title: Toll-like receptor 3 signal augments radiation-induced tumor growth retardation in a murine model
Authors: Yoshida, Sumito Browse this author
Shime, Hiroaki Browse this author →KAKEN DB
Takeda, Yohei Browse this author
Nam, Jin-Min Browse this author
Takashima, Ken Browse this author
Matsumoto, Misako Browse this author →KAKEN DB
Shirato, Hiroki Browse this author →KAKEN DB
Kasahara, Masanori Browse this author →KAKEN DB
Seya, Tsukasa Browse this author →KAKEN DB
Keywords: cytotoxic T lymphocyte
dendritic cell
radiation
Toll-like receptor 3
tumor necrosis factor‐α
Issue Date: Apr-2018
Publisher: John Wiley & Sons
Journal Title: Cancer science
Volume: 109
Issue: 4
Start Page: 956
End Page: 965
Publisher DOI: 10.1111/cas.13543
Abstract: Radiotherapy induces anti-tumor immunity by induction of tumor antigens and damage-associated molecular patterns (DAMP). DNA, a representative DAMP in radiotherapy, activates the stimulator of interferon genes (STING) pathway which enhances the immune response. However, the immune response does not always parallel the inflammation associated with radiotherapy. This lack of correspondence may, in part, explain the radiation-resistance of tumors. Additive immunotherapy is expected to revive tumor-specific CTL facilitating radiation-resistant tumor shrinkage. Herein pre-administration of the double-stranded RNA, polyinosinic-polycytidylic acid (polyI:C), in conjunction with radiotherapy, was shown to foster tumor suppression in mice bearing radioresistant, ovalbumin-expressing Lewis lung carcinoma (LLC). Extrinsic injection of tumor antigen was not required for tumor suppression. No STING- and CTL-response was induced by radiation in the implant tumor. PolyI:C was more effective for induction of tumor growth retardation at 1 day before radiation than at post-treatment. PolyI:C targeted Toll-like receptor 3 with minimal effect on the mitochondrial antiviral-signaling protein pathway. Likewise, the STING pathway barely contributed to LLC tumor suppression. PolyI:C primed antigen-presenting dendritic cells in draining lymph nodes to induce proliferation of antigen-specific CTL. By combination therapy, CTL efficiently infiltrated into tumors with upregulation of relevant chemokine transcripts. Batf3-positive DC and CD8+ T cells were essential for therapeutic efficacy. Furthermore, polyI:C was shown to stimulate tumor-associated macrophages and release tumor necrosis factor alpha, which acted on tumor cells and increased sensitivity to radiation. Hence, polyI:C treatment prior to radiotherapy potentially induces tumor suppression by boosting CTL-dependent and macrophage-mediated anti-tumor responses. Eventually, polyI:C and radiotherapy in combination would be a promising therapeutic strategy for radiation-resistant tumors.
Rights: http://creativecommons.org/licenses/by-nc/4.0/
Type: article
URI: http://hdl.handle.net/2115/70877
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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