Researchers at USC have uncovered a new way to develop more effective tumor vaccines by turning off the suppression function of regulatory T cells.

The results of the study were published in Nature Medicine on March 2.

“Under normal circumstances, regulatory T cells inhibit the immune system to attack its own cells and tissues to prevent autoimmune diseases,” said Si-Yi Chen, professor of immunology and molecular microbiology at the USC/Norris Comprehensive Cancer Center and the Keck School of Medicine of USC. “Cancer cells take advantage of regulatory T cells’ suppressor ability, recruiting them to keep the immune system at bay or disabling the immune system’s attack provoked by tumor vaccines.

“Our study provides a new vaccination strategy to overcome the regulatory T cells’ immune suppression while avoiding non-specific overactivation of autoreactive T cells and pathological autoimmune toxicities.”

The study identified a new molecular player called A20, an enzyme that restricts inflammatory signal transduction in dendritic cells.

When it is inhibited, the dendritic cells overproduce an array of cytokines and co-stimulatory molecules that trigger unusually strong immune responses that cannot be suppressed by regulatory T cells.

The resulting hyperactivated immune responses triggered by A20-deficient dendritic cells are capable of destroying various types of tumors that are resistant to current tumor vaccines in mice.

The immune system’s dendritic cells are the guardian cells of the immune systems and play an important role in activating immune responses to recognize and destroy tumor cells. Tumor vaccines have been designed and developed to incite the immune response to cancer cells so that the immune system can attack and destroy them.

However, discovering A20’s role in restricting immune responses has led to a method for blocking tumors from using regulatory T cells for protection.

“Despite intensive efforts, tumor vaccines have been largely ineffective in causing tumor regression in the clinic,” Chen said. “The vaccination approach we developed inhibits the key inhibitor in tumor antigen-loaded dendritic cells to selectively hyperactivate immune responses and to tip the balance from immune suppression in tumor-bearing hosts or cancer patients to effective antitumor immunity.”

This approach is capable of overcoming the regulatory T cells’ suppression mechanism and will allow for a new generation of tumor vaccines to be developed. The next step is to translate these findings into a human clinical trial, Chen said.

The National Institutes of Health and the Leukemia and Lymphoma Society funded the study.