TLR7 ligand augments GM-CSF-initiated antitumor immunity through activation of plasmacytoid dendritic cells.
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.
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Megumi
M
Narusawa
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, JapanAuthors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, JapanAuthors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Hiroyuki
H
Inoue
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Chika
C
Sakamoto
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Yumiko
Y
Matsumura
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Atsushi
A
Takahashi
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Tomoko
T
Inoue
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Ayumi
A
Watanabe
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Shohei
S
Miyamoto
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Yoshie
Y
Miura
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Yasuki
Y
Hijikata
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Yoshihiro
Y
Tanaka
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Makoto
M
Inoue
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Koichi
K
Takayama
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Toshihiko
T
Okazaki
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Mamoru
M
Hasegawa
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan.
Yoichi
Y
Nakanishi
Authors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, JapanAuthors' Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences; Department of Advanced Cell and Molecular Therapy and Center for Clinical and Translational Research, Kyushu University Hospital, Kyushu University, Fukuoka; and DNAVEC Corporation, Tsukuba, Japan taniken@bioreg.kyushu-u.ac.jp.
Kenzaburo
K
Tani
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D000077271:Imiquimod; D007167:Immunotherapy / Q000379:methods; D007369:Interferon Inducers / Q000494:pharmacology; D007370:Interferon Type I / Q000096:biosynthesis / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency; D029082:Sendai virus; D051199:Toll-Like Receptor 7; D014162:Transfection; D015854:Up-Regulation
D000634:Aminoquinolines; D015703:Antigens, CD; D019496:Cancer Vaccines; D007369:Interferon Inducers; D007370:Interferon Type I; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D053633:Receptor, Interferon alpha-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077271:Imiquimod