title: A new adjuvant delivery system 'cyclic di-GMP/YSK05 liposome' for cancer immunotherapy.
abstract: Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. It is thought that c-di-GMP is recognized by ATP dependent RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers a signal via the tank binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as an adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm. Our group has been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic, pH sensitive lipid that has a high fusogenicity. We utilized this lipid as a carrier to transport c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/cholesterol=40/25/35 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of the STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Miyabe
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Laboratory of Bioorganic Chemistry, Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, Toyota, Japan, 470-0392.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan; Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002460:Cell Line; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D007167:Immunotherapy; D016899:Interferon-beta / Q000378:metabolism; D008055:Lipids; D008081:Liposomes; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D010047:Ovalbumin / Q000008:administration & dosage; D010880:Piperidines; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D008055:Lipids; D008081:Liposomes; D010880:Piperidines; C580570:YSK05; C062025:bis(3',5')-cyclic diguanylic acid; D016899:Interferon-beta; D010047:Ovalbumin; D006152:Cyclic GMP
keywords: Adjuvant; Anti-tumor activity; C-di-GMP; Liposome