One of the ways cancer cells are effective at suppressing the host immune response is by turning off a surface protein called CTLA-4. It was previously believed that CTLA-4 was only expressed on T cells and other cells of the same lineage, but scientists at Baylor College of Medicine now show that it is also produced and secreted by dendritic cells. The findings may lead to a more effective combination therapy against cancer.
"These results are relevant to the battle against cancer because we showed that dendritic cell CTLA-4 performs a very critical regulatory function," William Decker, senior author of the paper and assistant professor at the Baylor College of Medicine, said in a release. "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."
Ipilimumab is an FDA-approved drug that is thought to work in melanoma by binding CTLA-4 on T-cells and protecting it from being turned off by cancer signals. Bristol-Myers Squibb ($BMY) markets the drug as Yervoy.
Decker published his group's work in the journal Stem Cells and Development earlier this week.
With this study, Decker and his team prove that dendritic cells, known to direct the activity of T cells, can produce and secrete CTLA-4 itself. The secretion of CTLA-4 in microvesicle packages then leads to a negative feedback loop by signaling to other dendritic cells to turn them off, resulting in T cells not being activated.
They compared mice given a vaccine made from dendritic cells that produced normal amounts of CTLA-4 with mice given a vaccine made from dendritic cells which made a reduced amount of CTLA-4. In mice bred to develop melanoma, those that got the normal dendritic cell vaccine were unable to slow the growth of the tumor, while mice in the latter group had marked improvement in launching an immune attack against the cancer cells.
“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," said Matthew Halpert, the first author of the study.
The Baylor team is now researching different approaches to combine removing CTLA-4, or inhibiting it with ipilimumab, with specific tumor vaccines, in order to maintain an effective immune response.