Scientists at St. Jude Children's Research Hospital announced on Apr. 2 that they have identified a way to enhance the effectiveness of cancer immunotherapy by improving the energy production of dendritic cells, which are key immune system gatekeepers. The findings were published in Science.
The research is significant because dendritic cells play a crucial role in activating cytotoxic immune cells that target and destroy cancer. However, tumors can suppress this process by reducing the mitochondrial function of dendritic cells, weakening the body's natural defenses against cancer.
The team found that within the tumor microenvironment—a nutrient-poor area surrounding cancer cells—dendritic cells lose their ability to produce energy efficiently through their mitochondria. This loss leads to dysfunction and hampers anticancer immunity. To address this, researchers introduced dendritic cells with enhanced mitochondrial activity into tumors in preclinical mouse models, resulting in restored immune response and improved tumor control.
The study also explored combining these high-mitochondrial-activity dendritic cells with existing immunotherapies such as immune checkpoint blockade. "We saw the most pronounced therapeutic effect in mice treated with the combination of dendritic cells that had high mitochondrial activity and immune checkpoint blockade," said co-first author Zhiyuan You, PhD, from the St. Jude Department of Immunology. "Those combinations synergistically slowed or stopped tumor growth and extended survival far more than either treatment alone." Further experiments showed that treated mice could resist new tumor growth months later, suggesting durable long-term immunity.
To understand how tumors impair dendritic cell function, researchers identified a signaling axis involving two proteins—OPA1 and NRF1—that regulates communication between mitochondria and the nucleus within these immune cells. The expression of these proteins was found to be significantly reduced during tumor progression, effectively triggering an 'energy crisis' mode where nonessential functions like immunogenic activity are shut down.
"We're seeing a direct regulation of dendritic cells by the tumor microenvironment," said co-first author Jiyeon Kim, PhD, also from St. Jude's Department of Immunology. "We have characterized how that results in mitochondrial reprogramming of dendritic cells to benefit cancer, giving us new opportunities to reverse the process." Chi added: "These findings reinforce the central role of dendritic cells in cancer immunity... we have provided a proof-of-principle of how we may be able to improve the next generation of immunotherapies."
