Research News

A new study from Cleveland Clinic dermatologists and researchers reports that melanoma patients with variants in cancer susceptibility genes have better overall outcomes from immune checkpoint inhibitor therapy. A research team led by Joshua Arbesman, MD, determined that the improved treatment response is driven by testable biomarkers like immune cell makeup. Their findings were published in the Journal of Investigative Dermatology. 

How does knowing that melanoma can be genetic improve patient care? 

Dr. Arbesman, a dermatologist, has shown that melanoma can be genetic and is in fact one of the most heritable types of cancer. Up to 15% (1 in 7) of all melanoma cases are associated with inherited genetic mutations called germline pathogenic variants (gPVs).  

“Some insurance companies still don’t cover genetic testing for these gPVs because we only just discovered that genetic predisposition to melanoma is more common than we thought,” Dr. Arbesman says, referring to the fact that physicians don’t normally offer genetic screening for cancers that don't meet a heritability threshold of at least 5%. “Studying how this subtype of cancer works will help justify genetic testing. It can also provide general information about how cancer works that will inform clinicians on how to treat all forms of melanoma, heritable or not.” 

How do immune checkpoint inhibitors work for melanoma cells? 

Dr. Arbesman’s team had previously shown that gPV-positive individuals with familial melanoma have significantly higher chances of melanoma-specific survival.  

Immune checkpoint inhibitors work by turning off proteins (immune checkpoints) on the surface of immune and tumor cells, including PD-1 and PDL-1. These proteins normally prevent our immune system from attacking tumor cells. In melanoma, selectively turning off this process allows for a more robust response to eliminate cancer cells evading our immune system, Dr. Arbesman says.  

“Immune checkpoint inhibitors have revolutionized how we treat melanoma, but we want to predict more accurately when to use it,” he explains. “Investigating further into gPV positive patients helps us identify when treatment is going to be more effective and help us weigh the side effects of prescribing it.” 

How can germline testing support immunotherapy for melanoma? 

Results from Dr. Arbesman’s most recent paper showed that gPV-positive individuals respond better to treatment even when considering factors outside survival. gPV-negative individuals experienced faster disease progression and needed to switch to a different medication sooner than gPV-positive individuals. This metric, called “time to next treatment” (TTNT), is a common factor used in clinical trials to measure how well a drug works in a patient. 

Dr. Arbesman and his team found that gPV-positive individuals have fewer myeloid-derived suppressor cells (MDSCs). MDSCs are cancer-specific immune cells that prevent healthy immune cells from attacking the tumor. Having fewer MDSCs to resist immunotherapy should mean that gPV-positive melanoma cells respond better to immune checkpoint inhibitors, Dr. Arbesman explains. 

“Although germline testing in melanoma is not routinely performed, identifying the presence of gPVs is already useful for patient care because it could help us determine who will more likely respond to immunotherapy for melanoma and may influence who receives it,” Dr. Arbesman says. “Further research into how these inherited genetic factors influence MDSC formation and overall treatment response may help us figure out how to sensitize gPV-negative individuals to treatment and improve their response to immunotherapy.”