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: 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, Ken J Ishii
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 31 Pg. 48860-48869 (Aug 02 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27384490 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• Cytokines
• Interferon Type I
• Oligodeoxyribonucleotides
• TLR9 protein, human
• Toll-Like Receptor 9
• Interleukin-12
• Sizofiran
• Interferon-gamma
• Leukocyte Common Antigens
• PTPRC protein, human

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Antibody Formation
• CD8-Positive T-Lymphocytes (immunology)
• CpG Islands (drug effects)
• Cytokines (pharmacology)
• Humans
• Immunity, Innate
• Interferon Type I (pharmacology)
• Interferon-gamma (immunology)
• Interleukin-12 (immunology)
• Leukocyte Common Antigens (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nanoparticles (chemistry)
• Neoplasms (blood, immunology, therapy)
• Oligodeoxyribonucleotides (administration & dosage)
• Phagocytosis
• Sizofiran (pharmacology)
• Toll-Like Receptor 9 (agonists)
• Tumor Microenvironment (drug effects)