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, informs UCLA Health.

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.

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.

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.

Sayat

Link: https://www.uclahealth.org/news/release/dna-copy-number-changes-help-melanoma-develop-resistance