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

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• 作者：Takashi Nakamura^a ; ¹ ; Hiroko Miyabe^a ; ¹ ; Mamoru Hyodo^b ; Yusuke Sato^a ; Yoshihiro Hayakawa^b ; Hideyoshi Harashima^a ; ^{harasima@pharm.hokudai.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：STING ; c-di-GMP ; Liposome ; Adjuvant ; Melanoma ; Cancer immunotherapy
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：28 October 2015
• 年：2015
• 卷：216
• 期：Complete
• 页码：149-157
• 全文大小：1351 K

文摘

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.