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, Kenzaburo Tani

研究成果: Contribution to journalArticle

10 引用 (Scopus)

抜粋

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 a 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 immunother-apy.

元の言語英語
ページ(範囲)568-580
ページ数13
ジャーナルCancer Immunology Research
2
発行部数6
DOI
出版物ステータス出版済み - 6 2014

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cancer Research

フィンガープリント TLR7 ligand augments GM-CSF-initiated antitumor immunity through activation of plasmacytoid dendritic cells' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用

    Narusawa, M., Inoue, H., Sakamoto, C., Matsumura, Y., Takahashi, A., Inoue, T., Watanabe, A., Miyamoto, S., Miura, Y., Hijikata, Y., Tanaka, Y., Inoue, M., Takayama, K., Okazaki, T., Hasegawa, M., Nakanishi, Y., & Tani, K. (2014). TLR7 ligand augments GM-CSF-initiated antitumor immunity through activation of plasmacytoid dendritic cells. Cancer Immunology Research, 2(6), 568-580. https://doi.org/10.1158/2326-6066.CIR-13-0143