Cellular Discovery May Lead to New Treatments for Melanoma

CTLA-4 molecule on T cells offer potential therapeutic target.

In addition to T cells, a molecule on these cells called CTLA-4 may also be produced and created by dendritic cells, according to a recent study.

T cells fight cancer cells within the body, but the cells are able to fight back by pushing a brake and turning the T cells off. The ‘brake’ is the CTLA-4 molecule.

A study published in Stem Cells and Development provided evidence that dendritic cells, which are responsible for directing the activity of T cells, produce and release CTLA-4. Once the dendritic cells are activated, they secrete CTLA-4 studded microvesicles into their environment. The microvesicles then can bind to other dendritic cells, be internalized, and turn off the cells, which are then unable to activate T cells.

Researchers studied a mouse model of melanoma to show the relevance of turning off dendritic cells.

“We tested 2 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,” said first study author Matthew M. Halpert.

The mice were broken into 2 groups, with 1 group receiving melanoma cells and a vaccine against the tumor made with normal dendritic cells, while the second group was given melanoma cells and a vaccine made with dendritic cells that produce small amounts of CTLA-r.

“The mice that received normal dendritic cells, which produce CTLA-4, were not able to slow down the growth of the tumor,” Halpert said. “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.”

The promising results have pushed researchers to suggest that strategies combing the removal of CTLA-4 or blocking it with the melanoma drug ipilimumab — with specific tumor vaccines – could result in better immune response that control tumor growth.

“These results are relevant to the battle against cancer because we showed that dendritic cell CTLA-4 performs a very critical regulatory function,” said senior study author William K. Decker. “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.”