title: Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity.
abstract: Among cancer immunotherapies, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8+T cells in concert with CD4+T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity.
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Sakamoto
authors.affiliation: Project Division of ALA Advanced Medical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kohara
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.|Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Kyushu University, Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Narusawa
authors.affiliation: Project Division of ALA Advanced Medical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Project Division of ALA Advanced Medical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: L
authors.initials: L
authors.lastname: Hirose-Yotsuya
authors.affiliation: Project Division of ALA Advanced Medical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.|Project Division of ALA Advanced Medical Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tani
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D029082:Sendai virus / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology*; D014161:Transduction, Genetic / Q000379:methods*; D014611:Vaccination / Q000379:methods*
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor