title: Therapy of peritoneally disseminated colon cancer by TAP-deficient embryonic stem cell-derived macrophages in allogeneic recipients.
abstract: We established a method to generate a large quantity of myeloid lineage cells from mouse embryonic stem (ES) cells, termed ES cell-derived proliferating myeloid cell lines (ES-ML). ES-ML continuously proliferated in the presence of M-CSF and GM-CSF. ES-ML genetically modified to express an anti-HER2 (neu) mAb single-chain V region fragment reduced the number of cocultured mouse Colon-26 cancer cells expressing HER2. Stimulation of ES-ML with IFN-γ plus LPS or TNF resulted in almost complete killing of the Colon-26 cells by the ES-ML, and the cytotoxicity was mediated, in part, by NO produced by ES-ML. When ES-ML were injected into mice with i.p. established Colon-26 tumors, they efficiently infiltrated the tumor tissues. Injection of ES-ML with rIFN-γ and LPS inhibited cancer progression in the mouse peritoneal cavity. Coinjection of TNF-transfected or untransfected ES-ML with rIFN-γ inhibited cancer growth and resulted in prolonged survival of the treated mice. In this experiment, transporter associated with Ag processing (TAP)1-deficient ES-ML exhibited therapeutic activity in MHC-mismatched allogeneic recipient mice. Despite the proliferative capacity of ES-ML, malignancy never developed from the transferred ES-ML in the recipient mice. In summary, TAP-deficient ES-ML with anticancer properties exhibited a therapeutic effect in allogeneic recipients, suggesting the possible use of TAP-deficient human-induced pluripotent stem cell-derived proliferating myeloid cell lines in cancer therapy.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Haga
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Haruta
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Koba
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Takamatsu
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Tokunori
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan senjusat@gpo.kumamoto-u.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D053595:Embryonic Stem Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D039904:Pluripotent Stem Cells / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D018719:Erb-b2 Receptor Tyrosine Kinases; D057127:Single-Chain Antibodies; C477327:transporter associated with antigen processing (TAP); C524056:Erbb2 protein, mouse