Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

Novel strategies/approaches to are being actively explored to overcome the relapse of cancers, resulting in tumor cells escaping from traditional therapies and/or host immune-surveillance. This study exploited the feasibility of improving the efficacy of therapeutic dendritic cell (DC)-based cancer vaccines with a combined use of phytochemical shikonin as an adjuvant. Shikonin, a phytochemical purified from Lithospermum erythrorhizon, has been shown to confer diverse pharmacological activities, including anti-inflammation, anti-tumor and others. Immunogenic cell death is characterized by damage-associated molecular patterns (DAMPs), which can enhance the maturation and antigen uptake of DCs. The anti-tumor effect of shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested DAMPs, including HSP70, HSP90, GRP78, CRT and HMGB1, in the resultant tumor cell lysate (TCL), termed as SK-TCL. The combination treatment with DAMPs and LPS activates DCs to a high maturation status and enhances the priming of Th1/Th17 effector cells. SK-TCL-loaded mature DCs exhibit a high level of CD86 and histocompartibility complex class II and activate Th1 cells. The shikonin-TCL-loaded DC-based vaccines result in a strong induction of CTL activity of splenocytes, a retardation in tumor growth, and an increase in the survival time of test mice. Together, our findings suggest that the much enhanced immunogenicity and efficacy of the cancer vaccine formulation, i.e, the use of shikonin-derived tumor cell lysates for pulse of DCs, may suggest a new ex vivo approach for developing individualized, dendritic cell-based cancer vaccines.