title: DNA-Containing Exosomes Derived from Cancer Cells Treated with Topotecan Activate a STING-Dependent Pathway and Reinforce Antitumor Immunity.
abstract: Danger-associated molecular patterns derived from damaged or dying cells elicit inflammation and potentiate antitumor immune responses. In this article, we show that treatment of breast cancer cells with the antitumor agent topotecan (TPT), an inhibitor of topoisomerase I, induces danger-associated molecular pattern secretion that triggers dendritic cell (DC) activation and cytokine production. TPT administration inhibits tumor growth in tumor-bearing mice, which is accompanied by infiltration of activated DCs and CD8+T cells. These effects are abrogated in mice lacking STING, an essential molecule in cytosolic DNA-mediated innate immune responses. Furthermore, TPT-treated cancer cells release exosomes that contain DNA that activate DCs via STING signaling. These findings suggest that a STING-dependent pathway drives antitumor immunity by responding to tumor cell-derived DNA.
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.|Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kitai
authors.affiliation: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawasaki
authors.affiliation: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sueyoshi
authors.affiliation: Laboratory of Vaccine Science, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.affiliation: Laboratory of Vaccine Science, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Ken J
authors.identifier: 0000-0002-6728-3872
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; and.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.affiliation: Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; and.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan; tarokawai@bs.naist.jp.
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004273:DNA, Neoplasm / Q000276:immunology* / Q000302:isolation & purification; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D055354:Exosomes / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D007113:Immunity, Innate; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D019772:Topotecan / Q000008:administration & dosage*; D000099197:STING Protein
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; C530855:Sting1 protein, mouse; D000099197:STING Protein