Melanoma Reprograms Immune System to Evade Death

Melanoma cells have the ability to mask themselves from the immune system, enabling the disease to proliferate and metastasize.

Although new immunotherapies have been effective at harnessing immune cells to fight different types of cancer, the drugs typically only work in half of patients with melanoma and become ineffective in resistant disease.

New findings published in Immunity suggest a new way to keep the immune system on defense against melanoma. The researchers are now pursuing this approach in a phase 1 trial.

“Understanding how cancers suppress the immune system is the key to identifying more effective immuno-therapies,” said Brent Hanks, MD, PhD. “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 authors explored this approach in mouse models of melanoma and confirmed their findings in human cells. The study focused on the role of dendritic cells, which signal T-cells to attack when they sense potentially harmful pathogens.

Previous research revealed that melanomas have the ability to reprogram dendritic cells to disregard cancer cells, but the mechanisms underlying this process were unknown.

In the current study, the authors discovered that melanoma silences dendritic cells by acting on a signaling pathway in the tumor’s microenvironment.

The pathway is contingent on the IDO enzyme, which the authors said is controlled by fatty acid metabolism and plays a role in immune suppression. When the pathway is acted on by melanoma, it triggers a cascade of events that leads to silencing of the immune system, according to the study.

“The IDO enzyme has been a focus of research in recent years, and there are several drugs that are being investigated to target it,” Dr Hanks said. “Our research looked at how we might influence the immune suppression function of IDO by targeting it upstream, along the metabolic pathway that controls it.”

The authors then tested a molecule that inhibits melanoma cells from reprograming the pathway, while enhancing the effect of immunotherapies, according to the study.

“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,” Dr Hanks said.

The authors said that a phase 1 clinical trial evaluating the efficacy of an existing molecule that targets the pathway is being planned. The researchers also plan to determine whether the drug may amplify the effects of current immunotherapies, according to the study.

“While there is understandable excitement around new therapies that enlist the immune system to fight cancer, we are still in a situation where greater than half of patients don’t respond in melanoma and the response rate is even worse in other cancer types,” Dr Hanks said. “We need to figure out why that is, and figure out how to reverse it. We’re hoping this research is a good step in that direction.”