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

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)568-580
Number of pages13
JournalCancer Immunology Research
Volume2
Issue number6
DOIs
Publication statusPublished - Jun 2014

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Lewis Lung Carcinoma
Granulocyte-Macrophage Colony-Stimulating Factor
Dendritic Cells
Immunity
imiquimod
Ligands
Interferon Type I
Neoplasms
Vaccination
Sialic Acid Binding Immunoglobulin-like Lectins
Lymph Nodes
Interferon Receptors
Sendai virus
Regulatory T-Lymphocytes
Therapeutics
Oligonucleotide Array Sequence Analysis
Knockout Mice
Colonic Neoplasms
T-Lymphocytes
Phenotype

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cancer Research

Cite this

Narusawa, M., Inoue, H., Sakamoto, C., Matsumura, Y., Takahashi, A., Inoue, T., ... 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

TLR7 ligand augments GM-CSF-initiated antitumor immunity through activation of plasmacytoid dendritic cells. / Narusawa, Megumi; Inoue, Hiroyuki; Sakamoto, Chika; Matsumura, Yumiko; Takahashi, Atsushi; Inoue, Tomoko; Watanabe, Ayumi; Miyamoto, Shohei; Miura, Yoshie; Hijikata, Yasuki; Tanaka, Yoshihiro; Inoue, Makoto; Takayama, Koichi; Okazaki, Toshihiko; Hasegawa, Mamoru; Nakanishi, Yoichi; Tani, Kenzaburo.

In: Cancer Immunology Research, Vol. 2, No. 6, 06.2014, p. 568-580.

Research output: Contribution to journalArticle

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, vol. 2, no. 6, pp. 568-580. https://doi.org/10.1158/2326-6066.CIR-13-0143
Narusawa, Megumi ; Inoue, Hiroyuki ; Sakamoto, Chika ; Matsumura, Yumiko ; Takahashi, Atsushi ; Inoue, Tomoko ; Watanabe, Ayumi ; Miyamoto, Shohei ; Miura, Yoshie ; Hijikata, Yasuki ; Tanaka, Yoshihiro ; Inoue, Makoto ; Takayama, Koichi ; Okazaki, Toshihiko ; Hasegawa, Mamoru ; Nakanishi, Yoichi ; Tani, Kenzaburo. / TLR7 ligand augments GM-CSF-initiated antitumor immunity through activation of plasmacytoid dendritic cells. In: Cancer Immunology Research. 2014 ; Vol. 2, No. 6. pp. 568-580.
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AU - Watanabe, Ayumi

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AU - Tanaka, Yoshihiro

AU - Inoue, Makoto

AU - Takayama, Koichi

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