Differential effects of phytochemical shikonin on induction of immunogenic cell death versus autophagy: Potential application to DC‐based cancer vaccine.

Abstract

Tumor immunogenicity can be characterized by the exposure of damage‐associated molecular patterns (DAMPs) on cell surface, which can recruit dendritic cells (DCs) and enhance DC maturation. Recent studies have demonstrated that chemotherapy‐induced autophagy may positively regulate immunogenic cell death (ICD). We recently showed that shikonin (SHK) can confer anti‐tumor activity and be employed as an adjuvant of DC‐based tumor vaccine via the induction of ICD. In this study, we investigated possible mechanistic correlation between SHK‐induced autophagy and SHK‐induced ICD for tumor immunogenicity. SHK enhanced ROS‐related cell death and increased the exposure of DAMP proteins on cell surface of test cells. SHK‐treated tumor cells activated the phagocytosis activity and the release of IL‐1β and IL‐6 from dendritic cells. SHK‐treated tumor cells as tumor vaccine reduced tumor growth and prolonged the survival of test mice. SHK reduced the proteasome activity to result in accumulating ubiquitinylated proteins and skewed to induce autophagy formation in tumor cells. The aggregation of SHK‐induced, ubiquitinylated proteins were found to co‐localize with p62 protein. Blockage of autolysosome formation via chloroquine (CQ) in SHK‐treated tumor cells further enhanced the expression of DAMPs on tumor cell surface. In addition, CQ and SHK cotreated tumor cells further enhanced the phagocytosis activity and CD40 and TLR4 expression of DC. The much enhanced immunogenicity and efficacy of SHK and CQ may create a compelling strategy, i.e., via the use of a combinational treatment, for developing DC‐based cancer vaccines.