The reason why half of metastatic melanomas do not respond to therapies

An analysis of 1,225 patients with the deadliest form of skin cancer, metastatic melanoma, reveals for the first time that a common genetic trait exists in most of those who did not respond to cancer drugs called immune checkpoint inhibitors.

Although these drugs have proven highly effective in treating metastatic melanoma and other cancers, they are known to fail in nearly half of patients.

Led by researchers at NYU Langone Health (USA), the study published in ' Nature Medicine ' conducted a genetic analysis of blood samples from the CheckMate-067 trial being conducted at more than 100 medical centers in 19 countries.

The results showed that patients with a specific type of genetic mutation, called MT haplogroup T (HG-T), were 3.46 times less likely to respond to checkpoint therapy than those without HG-T.

Mutations are DNA alterations that can occur in abnormal cells. Researchers have identified specific mutations (HG-T) in the mitochondria of patients who do not respond to immunotherapy. Unlike nuclear DNA, mitochondrial DNA is inherited exclusively through the maternal line and has evolved into distinct global subgroups, classified from A to Z according to their shared mutations.

In this work, the researchers decided to focus on mitochondrial DNA not only because of its unique lineage, but also because of previous research showing it plays a role in immune cell development.

In the CheckMate trial, immunotherapies such as nivolumab and ipilimumab were used to prevent melanoma recurrence after surgery by encouraging the immune system to recognize and attack tumor cells again.

To validate the CheckMate results, they compared their initial results with samples from 397 age- and sex-matched patients with metastatic melanoma. The results again revealed the same relationship between immunotherapy resistance and HG-T.

"Checkpoint immunotherapy has become a mainstay of cancer treatment over the past decade, especially for patients with metastatic melanoma, but until now, it's been unclear why nearly half of patients don't respond to treatment," says researcher and epidemiologist Kelsey Monson.

“ Our findings make it possible to conduct future tests for the presence of the TM haplogroup T to determine which patients with metastatic melanoma are most likely to fail checkpoint therapy, so that alternative treatment options can be considered, which in turn could improve overall outcomes,” adds Tomas Kirchhoff.

"The results of this study also raise the possibility that other mitochondrial haploid variants may influence patients' response to other immunotherapies," Kirchhoff notes.