New Genetic Discovery Holds Potential to Improve Immunotherapy Outcomes for Skin Cancer Patients

Recent research led by NYU Langone Health has revealed a significant genetic trait that could explain why many patients with metastatic melanoma do not respond to immunotherapy, a common treatment approach. This discovery may aid in refining treatment plans and improving overall patient outcomes.

The groundbreaking study involved analyzing blood samples from 1,225 patients diagnosed with the most aggressive form of skin cancer—metastatic melanoma. It was found that patients possessing a specific genetic mutation named MT haplogroup T (HG-T) were 3.46 times less likely to respond positively to immune checkpoint inhibitors compared to those without this trait. This type of mutation occurs within the cell's mitochondria, which is unique because it is inherited maternally.

Understanding how such mutations affect treatment efficacy is critical, especially as nearly 10,000 Americans succumb to this disease each year. Researchers focused their attention on mitochondrial DNA not just due to its maternal lineage but also because of its established role in immune cell development. Immune checkpoint inhibitors, such as nivolumab and ipilimumab, have become a staple for cancer care by enabling immune cells to detect and combat cancerous cells, which often evade the immune response through molecular 'checkpoints'. The study's initial findings were published in the journal Nature Medicine.

In the ongoing CheckMate-067 Phase 3 trial, patients were treated with these immunotherapies either alone or in combination to stave off cancer recurrence after surgery. The researchers validated their results by comparing samples from 397 metastatic melanoma patients with an equivalent demographic, further reinforcing the strong correlation between the HG-T variation and resistance to immunotherapy.

The implications of this research are significant. Kelsey Monson, PhD, one of the study's lead investigators, emphasized that the findings provide crucial insight to explain the treatment's failure in nearly half of the patients. As Robert Ferguson, PhD, another investigator, pointed out, this could lead to the development of a genetic biomarker test for HG-T, allowing clinicians to determine which patients might benefit from alternative treatments.

Moreover, the study indicates that patients with the HG-T mutation exhibited less developed T cells than those without it, potentially linked to enhanced protection against reactive oxygen species (ROS)—chemicals implicated in inflammatory responses that can hinder immune action against tumors. As a next step, researchers plan to conduct prospective clinical trials to explore whether patients without the HG-T mutation can expect better outcomes from immunotherapy than those with it.

Such research could illuminate the relationship between mitochondrial genetics and the immune system's response to cancer therapies more broadly. Current findings suggest that this phenomenon may not be limited to melanoma and could extend to other forms of cancer as well.

The study received backing from various National Institutes of Health grants and sponsorship from Bristol Myers Squibb, the manufacturer of the immunotherapies in the trial. NYU Langone Health, recognized nationally for its patient outcomes, continues to lead in the medical research landscape, delivering promising advancements in cancer care.

Continued discourse and collaborations among institutions worldwide are essential for expanding our understanding of cancer genetics and enhancing treatment modalities. As cancer research evolves, patient-centric precision medicine approaches will likely become the focal point in managing complex diseases like metastatic melanoma.