title: Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells.
abstract: Recent evidence suggest that a β-glucan derived from mushroom Schizophyllan(SPG) complexed with a humanized TLR9 agonistic CpG DNA, K3 (K3-SPG) is a promising vaccine adjuvant that induces robust CD8 T cell responses to co-administered antigen. However, it has not been investigated whether K3-SPG alone can act as an anti-cancer immunotherapeutic agent or not. Here, we demonstrate that intravenous injection of K3-SPG, but not CpG alone, is accumulated in the tumor microenvironment and triggered immunogenic cell death (ICD) of tumor cells by local induction of type-I interferon (IFN) as well as IL-12. Resultant innate immune activation as well as subsequent tumor-specific CD8 T cell responses were contributed the tumor growth suppression. This anti-tumor effect of K3-SPG monotherapy was also confirmed by using various tumor models including pancreatic cancer peritoneal dissemination model. Taken together, nano-particulate TLR9 agonist injected intravenously can scout out tumor microenvironment to provoke local innate immune activation and release dead tumor cells into circulation that may induce broader and protective tumor antigen-specific CD8 T cells.
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kitahata
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kanuma
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Department of Pediatrics, Yokohama City University, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ozasa
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Takato
authors.initials: T
authors.lastname: Kusakabe
authors.affiliation: Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Burcu
authors.initials: B
authors.lastname: Temizoz
authors.affiliation: Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Etsushi
authors.initials: E
authors.lastname: Kuroda
authors.affiliation: Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaue
authors.affiliation: Laboratory of Malaria Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.affiliation: Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.|Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D010587:Phagocytosis; D012566:Sizofiran / Q000494:pharmacology*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D018664:Interleukin-12; D012566:Sizofiran; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
keywords: CpG-ODN; immunogenic cell death; innate immunity; phagocytes; β-glucan