title: Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18.
abstract: Recent clinical trials and animal models demonstrated that immune checkpoint blockade enhanced effector cell responses and tumor rejection; however, further development and improvement of cancer immunotherapy is necessary for more favorable objective responses. In this study, we examined the effect of IL18 on the antitumor effect of immune checkpoint inhibitors.
  
  
  
  We examined the effect of IL18 on the peritoneal dissemination of CT-26 cells or tail vein injection metastasis of B16/F10 cells using antiprogrammed death-1 ligand-1 (αPD-L1) and/or anti-CTL-associated antigen-4 (αCTLA-4) mAbs.
  
  
  
  Massive ascites developed after intraperitoneal inoculation of CT-26, resulting in animal death within 30 days. Treatment of mice with αPD-L1 and/or αCTLA-4 significantly prolonged their survival, and a combination of the antibodies and IL18 provided a much greater therapeutic benefit. The combination modality led to the accumulation of precursor of mature natural killer (pre-mNK) cells in the peritoneal cavity together with increased CD8(+) T and decreased CD4(+)CD25(+)Foxp3(+) T cells. Depletion of the pre-mNK cells abrogated the therapeutic effects and increased the number of CD4(+)CD25(+)Foxp3(+) T cells. The combination treatment also suppressed tail vein injection metastasis of B16/F10 cells.
  
  
  
  The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memory-type CD8(+) T cells, and suppression of CD4(+)CD25(+)Foxp3(+) T cells. A combination of immune checkpoint inhibitors with IL18 may give a suggestion to the development of next-generation cancer immunotherapy. Clin Cancer Res; 22(12); 2969-80. ©2016 AACR.
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan. Department of Orthopaedic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshiya
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hata
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Yosif
authors.initials: Y
authors.lastname: El-Darawish
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Tzvetanka
authors.initials: T
authors.lastname: Markova
authors.affiliation: Hirakata Ryoikuen, Osaka, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamanishi
authors.affiliation: Hirakata Ryoikuen, Osaka, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yamanishi
authors.affiliation: Department of Surgery and Bioengineering, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tahara
authors.affiliation: Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, Hyogo College of Medicine, Hyogo, Japan. haruoka@hyo-med.ac.jp.
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D045744:Cell Line, Tumor; D007167:Immunotherapy / Q000379:methods; D020382:Interleukin-18 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D020382:Interleukin-18