title: Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor.
abstract: OBJECTIVE
  The purpose of the present study was to establish an effective immunotherapy by skewing the cosignal balance to be on the positive side by using the combination of monoclonal antibody (mAb) against 4-1BB also known as Cluster of Differentiation (CD) 137 as a co-stimulatory effector and to programmed death-1 (PD-1) to blockade the immune checkpoint.
  
  
  METHODS
  Mice implanted with 1×10(5) CT26 cells were treated with anti 4-1BB mAb alone, anti PD-1 mAb alone, or both anti 4-1BB mAb and anti PD-1 mAb. Immune cell populations were analyzed by flow cytometry. Tumor-infiltrating T-cells were evaluated by immunohistochemistry.
  
  
  RESULTS
  Mice treated with the combination therapy had the best antitumor response that resulted in complete tumor rejection. The numbers of CD4(+) interferon (IFN)-γ(+) and CD8(+) IFN-γ(+) T-cells were significantly higher in the combination group. The number of tumor-infiltrating T-cells was significantly increased in the combination therapy.
  
  
  CONCLUSIONS
  The therapeutic strategy of targeting co-signal molecules has promising clinical applications in the future.
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Yoshitaro
authors.initials: Y
authors.lastname: Shindo
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center in Tsukiji, National Cancer Center, Chuo-ku, Tokyo, Japan kyoshim6705@gmail.com.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Molecular Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kuramasu
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Oga
authors.affiliation: Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yoshino
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.affiliation: Department of Immunology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
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: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D007167:Immunotherapy; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists* / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
keywords: 4-1BB; Cancer immunotherapy; PD-1; immune checkpoint