title: IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression.
abstract: Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL-17A was critical for amplifying such local inflammation, as observed in the production of IL-1β and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23-dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30(+) Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsunekawa
authors.affiliation: Department of Surgery and Bioengineering, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Marimo
authors.initials: M
authors.lastname: Sato-Matsushita
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
authors.affiliation: Pathway Biology, Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
authors.affiliation: Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori, Japan.|Chromosome Engineering Research Center, Tottori University, Yonago, Tottori, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Okada
authors.affiliation: Department of Surgery and Bioengineering, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tahara
authors.affiliation: Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan. haya@inm.u-toyama.ac.jp.|Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan. haya@inm.u-toyama.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D007109:Immunity; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis*; D017730:Ki-1 Antigen / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D020381:Interleukin-17; D017730:Ki-1 Antigen
keywords: CD30; IL-17; IL-1β; neutrophil; γδ T cell