Potential Biomarker predicts resistance to immunotherapies in melanoma

Duke Cancer Institute researchers have identified potential biomarkers that predict the likelihood for checkpoint inhibitor drugs to backfire, driving hyper-progression of melanoma cells instead of unleashing the immune system to fight them.

The new study in mice and human tissue points to a strategy for inhibiting hyper-progression, potentially benefitting an estimated 10% of cancer patients who undergo this devastating complication from checkpoint inhibitor immunotherapies.

Checkpoint inhibitors have been a cancer success story, but hyper-progression has been a troubling side effect in some patients. Hanks and colleague investigated the underlying mechanism for this process in melanoma, identifying a protein complex that is rooted in cancer tumors called the NLRP3 inflammasome.

Inflammasomes are danger sensors that typically help the immune system recognize foreign invaders. In certain cases, however, the researchers found that the NLRP3 inflammasome in tumors reacts to activated T-cell responses and triggers a cascade of events that results in resistance to the checkpoint inhibitors. The inflammasome process then goes into full-out protective mode where it builds an environment that helps cancer cells spread.

Once the process and key actors were identified, the researchers sought a way to identify which patients were at risk for developing hyper-progression prior to initiating checkpoint inhibitor immunotherapy. Using tumor tissue samples from stage IV melanoma patients at Duke, the researchers found that high baseline concentrations of the molecules involved in the inflammasome process were associated with the development of disease hyper-progression and inferior survival.

Reference:

Brent Hanks, et al, JOURNAL Science Translational Medicine