Priority Research Papers:

Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells

Yuji Kitahata, Tomohiro Kanuma, Masayuki Hayashi, Nobuyoshi Kobayashi, Koji Ozasa, Takato Kusakabe, Burcu Temizoz, Etsushi Kuroda, Hiroki Yamaue, Cevayir Coban, Takuya Yamamoto, Kouji Kobiyama, Taiki Aoshi and Ken J. Ishii _

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Oncotarget. 2016; 7:48860-48869. https://doi.org/10.18632/oncotarget.10379

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Yuji Kitahata1,2, Tomohiro Kanuma1,3, Masayuki Hayashi1, Nobuyoshi Kobayashi1, Koji Ozasa1,5, Takato Kusakabe1,3, Burcu Temizoz3, Etsushi Kuroda3, Hiroki Yamaue2, Cevayir Coban4, Takuya Yamamoto1,3, Kouji Kobiyama1,3, Taiki Aoshi1,3 and Ken J. Ishii1,3

1 Labotatory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan

2 2nd Department of Surgery, Wakayama Medical University, Wakayama, Japan

3 Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan

4 Laboratory of Malaria Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

5 Department of Pediatrics, Yokohama City University, Yokohama, Japan

Correspondence to:

Ken J. Ishii, email:

Keywords: CpG-ODN, β-glucan, innate immunity, immunogenic cell death, phagocytes

Received: May 06, 2016 Accepted: June 18, 2016 Published: July 01, 2016


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.

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