論文

査読有り
2014年6月

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

CANCER IMMUNOLOGY RESEARCH
  • 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
  • ,
  • Kenzaburo Tani

2
6
開始ページ
568
終了ページ
580
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/2326-6066.CIR-13-0143
出版者・発行元
AMER ASSOC CANCER RESEARCH

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 IFN alpha 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. (C) 2014 AACR.

Web of Science ® 被引用回数 : 9

リンク情報
DOI
https://doi.org/10.1158/2326-6066.CIR-13-0143
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/24830413
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000340035300009&DestApp=WOS_CPL

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