Abstract
Exposure to ionizing radiation, a physical treatment that inactivates live tumor cells, has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials. However, the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored. Here, we demonstrate that oxidized mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING) signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine. Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells. Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells (DCs). Oxidized mtDNA, as a DAMP or adjuvant, activated the STING-TBK1-IRF3-IFN-β pathway in DCs, which subsequently cross-presented irradiated tumor cell-derived antigens to CD8+ T cells and elicited antitumor immunity. The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity, which may have implications for new strategies to improve the efficacy of irradiated vaccines.
Highlights
As a form of immunotherapy, cancer vaccines have demonstrated objective therapeutic benefits in several randomized clinical trials.[1,2] The activation of tumor-specific immune effects by cancer vaccines, whole-tumor cell vaccines that contain all potential tumor antigens, represents a promising approach for cancer therapy.[3]
We demonstrate that elevations in reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA) 8-OHG content can be induced in irradiated tumor cells, which are subsequently engulfed by dendritic cells (DCs)
We found that treatment of irradiated EG7 cells with the ROS scavenger Butylated hydroxyanisole (BHA) significantly impaired the irradiated EG7 cell vaccine-mediated antitumor effect (Fig. 7b), demonstrating that oxidative damage is important for the antitumor effect induced by the irradiated tumor cell vaccine
Summary
As a form of immunotherapy, cancer vaccines have demonstrated objective therapeutic benefits in several randomized clinical trials.[1,2] The activation of tumor-specific immune effects by cancer vaccines, whole-tumor cell vaccines that contain all potential tumor antigens, represents a promising approach for cancer therapy.[3] Ionizing radiation (IR), which inactivates live tumor cells to create cancer cell vaccines, has been used extensively to enhance antitumor immunity in both animal models and human clinical trials.[4,5,6,7,8] In addition, local radiotherapy used alone or in combination with surgery, chemotherapy, or targeted therapy is employed to treat the primary and metastatic tumors of cancer patients.[9,10,11] localized radiotherapy has been shown to induce abscopal effects in several types of cancer.[12,13] Overall, ionizing radiation can potentiate the antitumor response induced by either an irradiated tumor cell vaccine or local radiotherapy
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