RT Journal Article
SR Electronic
T1 TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 568
OP 580
DO 10.1158/2326-6066.CIR-13-0143
VO 2
IS 6
A1 Narusawa, Megumi
A1 Inoue, Hiroyuki
A1 Sakamoto, Chika
A1 Matsumura, Yumiko
A1 Takahashi, Atsushi
A1 Inoue, Tomoko
A1 Watanabe, Ayumi
A1 Miyamoto, Shohei
A1 Miura, Yoshie
A1 Hijikata, Yasuki
A1 Tanaka, Yoshihiro
A1 Inoue, Makoto
A1 Takayama, Koichi
A1 Okazaki, Toshihiko
A1 Hasegawa, Mamoru
A1 Nakanishi, Yoichi
A1 Tani, Kenzaburo
YR 2014
UL http://cancerimmunolres.aacrjournals.org/content/2/6/568.abstract
AB 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.