Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma.

Abstract

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.

• Authors: Takashi Nakamura, Hiroko Miyabe, Mamoru Hyodo, Yusuke Sato, Yoshihiro Hayakawa, Hideyoshi Harashima
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 216 Pg. 149-57 (Oct 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26282097 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Ligands
• Lipids
• Liposomes
• Membrane Proteins
• Piperidines
• STING1 protein, human
• YSK05
• bis(3',5')-cyclic diguanylic acid
• Cyclic GMP

Topics

• Animals
• Chemotherapy, Adjuvant
• Cyclic GMP (analogs & derivatives, pharmacology)
• Cytokines (blood)
• Cytosol (metabolism)
• Drug Delivery Systems
• Immunotherapy (methods)
• Injections, Intravenous
• Killer Cells, Natural (drug effects)
• Ligands
• Lipids
• Liposomes (chemistry)
• Lung (pathology)
• Macrophage Activation (drug effects)
• Melanoma, Experimental (pathology, therapy)
• Membrane Proteins (drug effects)
• Mice
• Neoplasm Metastasis
• Piperidines