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.