Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma.
Malignant melanomas escape immunosurveillance via the loss/down-regulation of MHC-I expression. Natural killer (NK) cells have the potential to function as essential effector cells for eliminating melanomas. Cyclic di-GMP (c-di-GMP), a ligand of the stimulator of interferon genes (STING) signal pathway, can be thought of as a new class of adjuvant against cancer. However, it is yet to be tested, because technologies for delivering c-di-GMP to the cytosol are required. Herein, we report that c-di-GMP efficiently activates NK cells and induces antitumor effects against malignant melanomas when loaded in YSK05 lipid containing liposomes, by assisting in the efficient delivery of c-di-GMP to the cytosol. The intravenous administration of c-di-GMP encapsulated within YSK05-liposomes (c-di-GMP/YSK05-Lip) into mice efficiently induced the production of type I interferon (IFN) as well as the activation of NK cells, resulting in a significant antitumor effect in a lung metastasis mouse model using B16-F10. This antitumor effect was dominated by NK cells. The infiltration of NK cells was observed in the lungs with B16-F10 melanomas. These findings indicate that the c-di-GMP/YSK05-Lip induces MHC-I non-restricted antitumor immunity mediated by NK cells. Consequently, c-di-GMP/YSK05-Lip represents a potentially new adjuvant system for use in immunotherapy against malignant melanomas.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Takashi
T
Nakamura
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Hiroko
H
Miyabe
Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, Toyota, Japan.
Mamoru
M
Hyodo
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yusuke
Y
Sato
Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, Toyota, Japan.
Yoshihiro
Y
Hayakawa
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
Hideyoshi
H
Harashima
D000818:Animals; D017024:Chemotherapy, Adjuvant; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D003600:Cytosol / Q000378:metabolism; D016503:Drug Delivery Systems; D007167:Immunotherapy / Q000379:methods*; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000187:drug effects; D008024:Ligands; D008055:Lipids; D008081:Liposomes / Q000737:chemistry*; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000187:drug effects*; D051379:Mice; D009362:Neoplasm Metastasis; D010880:Piperidines; D000099197:STING Protein
D006152:Cyclic GMP; D016207:Cytokines; D008024:Ligands; D008055:Lipids; D008081:Liposomes; D008565:Membrane Proteins; D010880:Piperidines; C532857:STING1 protein, human; D000099197:STING Protein; C580570:YSK05; C062025:bis(3',5')-cyclic diguanylic acid
Adjuvant; Cancer immunotherapy; Liposome; Melanoma; STING; c-di-GMP