title: A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice.
abstract: Interleukin (IL) 12 treatment in the CSA1M and OV-HM, but not in Meth A tumor models,induces tumor regression that is associated with T-cell migration to tumor sites.Here, we investigated the role of the CC chemokine receptor (CCR)5 in T-cell migration induced after IL-12 treatment. In the two IL-12-responsive tumor models (CSA1M and OV-HM), IL-12 treatment up-regulated the mRNA expression of CCR5 in splenic T cells as well as ligands for CCR5, such as macrophage inflammatory protein (MIP) 1alpha and MIP-1beta in tumor masses. In contrast, the expression of CCR5 in spleens and MIP-1alpha/MIP-1beta in tumor masses was marginally induced before and even after IL-12 treatment in the Meth A model in which T-cell migration is not observed. T cells infiltrating tumor masses in the former two IL-12-responsive models expressed CCR5. Administration of a synthetic CCR5 antagonist TAK-779 to tumor-bearing mice during IL-12 immunotherapy prevented T-cell migration and tumor regression. Furthermore, anti-CCR5 antibody was found to inhibit T-cell migration in the lymphoid cell migration assay. Namely, although splenic T cells prepared from IL-12-treated CSA1M or OV-HM-bearing mice migrated into the corresponding tumor masses in recipient mice, the migration was inhibited when donor T cells were treated with anti-CCR5 antibody before the injection. These results indicate a critical role for CCR5 in the induction of T-cell migration to tumor sites after IL-12 treatment.
authors.affiliation: Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uekusa
authors.forename: Wen-Gong
authors.initials: WG
authors.lastname: Yu
authors.forename: Takao
authors.initials: T
authors.lastname: Mukai
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Masako
authors.initials: M
authors.lastname: Murai
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Obika
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imanishi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Higashibata
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hamaoka
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000577:Amides; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D019713:Receptors, CCR5; D018664:Interleukin-12; C119369:TAK 779