Scientists now know how melanoma skin cancer evolves to resist immunotherapy

A study led by UCLA Health Jonsson Comprehensive Cancer Center investigators has revealed how melanoma, the deadliest form of skin cancer, evolves to resist immunotherapy. That research has led to the identification of a potential strategy to prevent or reverse that resistance.

The team found that relapsing melanoma tumors often acquire genomic DNA copy-number variants, which delete or amplify sections of DNA. These variants frequently affect genes that control cancer cells' ability to self-destruct in response to damage caused by immune attacks. The cumulative effect of copy-number changes, often involving multiple cell-death genes, allows cancer cells to survive immune attacks, leading to tumors relapsing or regrowing months or years after the initial therapy-induced tumor shrinkage.

The findings, published in the journal Immunity, suggest that making the tumor cells more prone to self-destruct following immune attacks could help maintain or restore the effectiveness of immune checkpoint inhibitors, a widely used form of cancer immunotherapy.

"Studies of how cancer genomes evolve to acquire resistance to therapies often focus on small-scale or point mutations," said Dr. Roger Lo, professor of medicine, dermatology and molecular & medical pharmacology at the David Geffen School of Medicine at UCLA and senior author of the study. "This study highlights how large-scale mutations, including gene copy-number changes, can be an efficient way for cancers to evolve."

Resistance to immunotherapy, especially immune checkpoint inhibitors, remains one of the greatest challenges in cancer treatment. While many patients with melanoma initially respond well to checkpoint inhibitors, 40-60% eventually experience relapse as the cancer adapts and becomes resistant.

Read the full story on the UCLA Health website.