Mechanistic Study of Shikonin-induced Autophagy versus Necroptosis on Tumor Immunogenicity and Its Application for DC-based Cancer Vaccine

• Main Authors: Sheng-Yen Lin, 林聖晏
• Other Authors: Ning-Sun Yang
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/arp4b7

博士 === 國防醫學院 === 生命科學研究所 === 105 === Programmed necrosis, necroptosis, is considered to be a highly immunogenic activity, often mediated via the release of damage-associated molecular patterns (DAMPs). Interestingly, enhanced autophagic activity is often found to be accompanied by necroptosis. However, the possible role of autophagy in the immunogenicity of necroptotic death remains largely obscure. In this study, we investigated the possible mechanistic correlation between phytochemical shikonin-induced autophagy and the shikonin-induced necroptosis for tumor immunogenicity. We show that shikonin could instigate receptor-interacting protein (RIPK)1- and RIPK3-dependent necroptosis that is accompanied by enhanced autophagy. Shikonin-induced autophagy could directly contribute to DAMP upregulation. Counterintuitively, among the released and ecto-DAMPs, only the latter were shown to be able to activate the co-cultured dendritic cells (DCs). Interruption of autophagic flux via chloroquine further upregulated ecto-DAMP activity and resultant DC activation. For potential clinical application, DC vaccine preparations treated with tumor cells that were already pre-treated with chloroquine and shikonin further enhanced the anti-metastatic activity of 4T1 tumors and reduced the effective dosage of doxorubicin. The enhanced immunogenicity and vaccine efficacy obtained via shikonin and chloroquine co-treatment of tumor cells may thus constitute a compelling strategy for developing cancer vaccines via the use of a combinational drug treatment.