title: Combination therapy with α-galactosylceramide and a Toll-like receptor agonist exerts an augmented suppressive effect on lung tumor metastasis in a mouse model.
abstract: α-galactosylceramide (GalCer), which is a natural killer T (NKT) cell ligand, has been reported to exert therapeutic effects against cancer in humans and mice. Toll-like receptor (TLR) agonists systemically or locally boost antitumor efficacy in mouse cancer models. In our previous study, the co-administration of GalCer and a TLR agonist synergistically enhanced interferon-γ (IFN-γ) production in mouse splenocytes in vitro and in vivo. The increased IFN-γ production promoted a tumor antigen-specific Th1 response. Therefore, co-treatment with GalCer and a TLR agonist is expected to exert an enhanced antitumor effect. In the present study, we examined the effect of GalCer and lipopolysaccharide (LPS) combination therapy in a mouse lung-metastasis model. GalCer and LPS combination therapy markedly decreased the number of lung metastatic tumor nodes. Co-treatment with GalCer and LPS enhanced the mRNA expression of CXCL9 and CXCL10 in mediastinal lymph nodes (MLNs) and increased the number of CD8+ cells in the MLNs. Furthermore, the depletion of CD8+ T cells canceled the antitumor effect of GalCer and LPS combination therapy. Thus, GalCer and LPS combination therapy significantly enhanced tumor antigen-specific immune responses and suppressed tumor growth in a mouse lung-metastasis model.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ando
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arioka
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ogiso
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D013154:Spleen / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists*
chemical_list: D000951:Antigens, Neoplasm; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; D005699:Galactosylceramides; D008024:Ligands; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; C493154:alpha-galactosylceramide; D007371:Interferon-gamma