Discovery of CTLA-4 in dendritic cells opens new possibilities to fight cancer

"These results are relevant to the battle against cancer because we showed that dendritic cell CTLA-4 performs a very critical regulatory function. Its presence inhibits the generation of downstream anticancer responses, whereas its absence permits robust priming of such responses. These new data provide a strong rationale to use the drug ipilimumab in new and better ways, for instance in conjunction with cancer vaccines," said Dr. William K. Decker, assistant professor of pathology & immunology at Baylor and the Center for Cell and Gene Therapy, a member of the Dan L Duncan Comprehensive Cancer Center, and senior author of this paper.

Ipilimumab is a Food and Drug Administration-approved drug to treat melanoma. Scientists think that ipilimumab helps the body fight cancer cells by removing the 'brake' cancer cells place on the T cells. Ipilimumab binds to CTLA-4 on T cells, blocking signals that turn off the T cells. As a result, scientists think, T cells resume their fight against the cancer.

In this study, Baylor researchers have contributed a new piece to the puzzle of how the immune system regulates T-cell responses. Decker and his colleagues provide solid evidence that dendritic cells, the 'generals' that direct the activity of the T cells, produce and release CTLA-4, which until now has been controversial. When activated, dendritic cells secrete CTLA-4-studded microvesicles into their environment. The microvesicles can bind to other dendritic cells, be internalized, and turn off the dendritic cells, which then cannot proceed to activate T cells.

"To show the relevance of turning off the dendritic cells in the body's response against tumors, we studied a mouse model of melanoma," said Dr. Matthew M. Halpert, an instructor in immunology and first author of the paper. "We tested two types of dendritic cells: normal dendritic cells expressing CTLA-4 and dendritic cells treated with CTLA-4 siRNA, a strategy that dramatically diminishes the production of CTLA-4. One group of mice received melanoma cells and a vaccine against the tumor made with normal dendritic cells. A second group of mice received melanoma cells and a vaccine made with dendritic cells that produce little amounts of CTLA-4. The mice that received normal dendritic cells, which produce CTLA-4, were not able to slow down the growth of the tumor. On the other hand, the mice treated with dendritic cells that produce little CTLA-4 were able to develop an immune response that markedly limited tumor growth. These results suggest that priming an immune response against melanoma in the absence of CTLA-4 triggers a response that can control tumor growth in this mouse model."

These results have encouraged the Baylor researchers to suggest that strategies that combine taking away CTLA-4, or blocking it with ipilimumab, with specific tumor vaccines, of which many already exist in experimental settings, may result in better immune responses that can control tumor growth.