Despite emerging therapies designed to activate the body’s own immune system to attack cancer cells, success has been limited in melanoma patients. It appears that tumors gain tolerance in particular to dendritic cells, allowing cancer to evade the immune system. A research team from Duke University has identified the cellular mechanism behind this tolerization, which may be harnessed as a new mode of cancer therapy.
"Understanding how cancers suppress the immune system is the key to identifying more effective immuno-therapies," said study senior author Brent Hanks. "Our research is an important step in that direction. We've identified a new mechanism of immunotherapy resistance that appears to be reversible, potentially enhancing the effect of the therapies we now have."
The mechanism, the team reports in Immunity, relies on the cellular response involving the regulatory enzyme IDO to paracrine signaling by melanoma cells. Melanoma release of Wnt glycoproteins triggers a fatty acid oxidation signaling cascade within the dendritic cells. The cascade results in the increased activity of IDO as well as decreased expression of cytokines, IL-6 and IL-12. Ultimately, this leads to greater conversion of naive CD4+ T cells to regulatory T cells. The latter are understood to be less effective in controlling cancer growth.
From identifying this mechanism, the team has been able to investigate a molecule designed to not just block IDO, but the pathway upstream. "We found that this pathway regulates not only IDO but also other important components of the immune system, suggesting that blocking this pathway may be superior to targeting IDO only," Hanks said.
The team’s paper concludes “that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model.”
A phase 1 clinical study designed to block this pathway is now in the planning stages.
Image: The process by which melanoma cells hijack dendritic cells, allowing cancer to avoid detection by the immune system. Image courtesy of Brent Hanks and Elsevier Cell Immunity.