Study reveals how melanoma evolves to resist immunotherapy

A study led by UCLA Health Jonsson Comprehensive Cancer Center investigators reveals how melanoma, the deadliest form of skin cancer, evolves to resist immunotherapy and identifies 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 the cancer cells' ability to self-destruct in response to damage caused by immune attack. 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 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. This study highlights how large-scale mutations, including gene copy-number changes, can be an efficient way for cancers to evolve." 

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

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.

To understand how tumors become resistant over time, the researchers analyzed tumor samples from patients before and after they experienced relapse following treatment with immune checkpoint inhibitors. They also analyzed tumors from surgeries that were followed by adjuvant checkpoint therapy and subsequently from biopsies at recurrences. They combined analysis of tumor-derived data from patients with analyses of published screening studies aimed at defining all cancer immunotherapy resistance genes as well as analyses of cell-culture and mouse models the UCLA team developed. 

The team then tested whether pharmacologically sensitizing tumors to programmed cell death or apoptosis would re-sensitize tumors to immunotherapy. In both cell-line and mouse models, lowering the apoptotic threshold of tumor cells reinstated killer immune or T cells' ability to induce apoptosis of cancer cells. In a mouse model of melanoma, the UCLA team was able to prevent tumor relapses if a pro-apoptotic drug was added to treat residual tumors that had responded to immunotherapy.

"These findings point to a promising preventive therapeutic strategy," said Dr. Lo, who is a member of the UCLA Health Jonsson Comprehensive Cancer Center. "If we can intervene early to target incipient resistant cancer cells in residual tumors, we may be able to extend the effective durability of immunotherapy in patients with melanoma."

The study also reveals the importance of tracking tumor evolution at the single-cell level. Using single-cell whole-genome sequencing, the team discovered that some of the resistance-related genetic changes were already present in small subsets of tumor cells before treatment began. In addition, relapsing tumors contain heterogeneous subclones with distinct permutations of critical DNA copy-number variations. The genomic copy-number variations contribute to resistance even before therapy begins and fuel natural selection for resistance evolution after therapy begins. For some patients, a wait-and-see or monitoring approach during remission may not be optimal. 

Future research will focus on expanding our analyses to include more patients, experimental models, and additional genomic techniques. Developing a clinical trial designed to lower the rate of relapses is another aim. 

The study's co-first authors are Mingming Wu, a postdoctoral researcher at UCLA, Shiyue (Sabrina) Yang, a UCLA doctoral candidate, Zhentao Yang, a project scientist in the division of dermatology at UCLA Health, and Jian Fan, a post-doctoral researcher at UCLA Health. Other UCLA authors are Shirley H. Lomeli, Prashanthi Dharanipragada, Gatien Moriceau, Robert Damoiseaux, and Sixue Liu. Other co-authors included collaborators from Vanderbilt-Ingram Cancer Center and California Pacific Medical Center.

The study was funded in part by grants from the National Institutes of Health, the V Foundation for Cancer Research, the Melanoma Research Alliance, and the Melanoma Research Foundation.