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Research Articles

TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells

Megumi Narusawa, Hiroyuki Inoue, Chika Sakamoto, Yumiko Matsumura, Atsushi Takahashi, Tomoko Inoue, Ayumi Watanabe, Shohei Miyamoto, Yoshie Miura, Yasuki Hijikata, Yoshihiro Tanaka, Makoto Inoue, Koichi Takayama, Toshihiko Okazaki, Mamoru Hasegawa, Yoichi Nakanishi and Kenzaburo Tani
Megumi Narusawa
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Hiroyuki Inoue
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Chika Sakamoto
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Yumiko Matsumura
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Atsushi Takahashi
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Tomoko Inoue
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Ayumi Watanabe
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Shohei Miyamoto
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Yoshie Miura
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Yasuki Hijikata
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Yoshihiro Tanaka
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Makoto Inoue
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Koichi Takayama
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Toshihiko Okazaki
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Mamoru Hasegawa
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Yoichi Nakanishi
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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Kenzaburo Tani
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
1Department of Molecular Genetics, Medical Institute of Bioregulation; 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; 3Department of Advanced Cell and Molecular Therapy and 4Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and 5DNAVEC Corporation, Tsukuba, Japan
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DOI: 10.1158/2326-6066.CIR-13-0143 Published June 2014
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Abstract

Vaccination with irradiated granulocyte macrophage colony-stimulating factor (GM-CSF)–transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We therefore attempted to improve the antitumor effect by identifying little-known key pathways in GM-CSF–sensitized dendritic cells (GM-DC) in tumor-draining lymph nodes (TDLN). We initially confirmed that syngeneic mice subcutaneously injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) remarkably rejected the tumor growth. Using cDNA microarrays, we found that expression levels of type I interferon (IFN)–related genes, predominantly expressed in plasmacytoid DCs (pDC), were significantly upregulated in TDLN-derived GM-DCs and focused on pDCs. Indeed, mouse experiments demonstrated that the effective induction of GM-CSF–induced antitumor immunity observed in immunocompetent mice treated with LLC/SeV/GM cells was significantly attenuated when pDC-depleted or IFNα receptor knockout (IFNAR−/−) mice were used. Importantly, in both LLC and CT26 colon cancer–bearing mice, the combinational use of imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype, in pDCs, but decreased the ratio of CD4+CD25+FoxP3+ regulatory T cells in TDLNs. Collectively, these findings indicate that the additional use of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the immunologic antitumor effects of GVAX therapy, shedding promising light on the understanding and treatment of GM-CSF–based cancer immunotherapy. Cancer Immunol Res; 2(6); 568–80. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received September 5, 2013.
  • Revision received February 5, 2014.
  • Accepted March 3, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Immunology Research: 2 (6)
June 2014
Volume 2, Issue 6
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TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells
Megumi Narusawa, Hiroyuki Inoue, Chika Sakamoto, Yumiko Matsumura, Atsushi Takahashi, Tomoko Inoue, Ayumi Watanabe, Shohei Miyamoto, Yoshie Miura, Yasuki Hijikata, Yoshihiro Tanaka, Makoto Inoue, Koichi Takayama, Toshihiko Okazaki, Mamoru Hasegawa, Yoichi Nakanishi and Kenzaburo Tani
Cancer Immunol Res June 1 2014 (2) (6) 568-580; DOI: 10.1158/2326-6066.CIR-13-0143

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TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells
Megumi Narusawa, Hiroyuki Inoue, Chika Sakamoto, Yumiko Matsumura, Atsushi Takahashi, Tomoko Inoue, Ayumi Watanabe, Shohei Miyamoto, Yoshie Miura, Yasuki Hijikata, Yoshihiro Tanaka, Makoto Inoue, Koichi Takayama, Toshihiko Okazaki, Mamoru Hasegawa, Yoichi Nakanishi and Kenzaburo Tani
Cancer Immunol Res June 1 2014 (2) (6) 568-580; DOI: 10.1158/2326-6066.CIR-13-0143
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