Researchers may have uncovered genetic differences that may help predict response to immune checkpoint inhibitors among patients with metastatic melanoma, according to a recent study published by Monson et al in Nature Medicine.
Background
The investigation revolved around mitochondrial haplogroups that have evolved in DNA inherited only from the mother. Mitochondrial DNA is different from nuclear DNA, which is passed down from both a mother and a father. Mitochondria have long been known to play a role in how immune cells develop. Recent evidence has suggested that mitochondrial genetics may be essential for immune cell function.
Study Methods and Results
Researchers performed a genetic analysis of blood samples from 1,225 patients participating in the phase III CheckMate-067 trial, which examined frontline use of immune checkpoint inhibitors to treat metastatic melanoma. They hypothesized that inherited genetic changes in mitochondrial DNA might affect immune cells’ ability to fight cancer in patients treated with immune checkpoint inhibitors.
The researchers discovered that inherited genetic differences in mitochondrial DNA—called mitochondrial haplogroup T—predicted resistance to immune checkpoint inhibitors. For instance, patients with mitochondrial haplogroup T were 3.46 times less likely to respond to treatment with nivolumab monotherapy or nivolumab in combination with ipilimumab compared with patients who had other mitochondrial haplogroups. Haplogroup T was found to be present in about 12% of the patients with metastatic melanoma.
“Our study offers the first scientific evidence of an inherited genetic marker, the presence of mitochondrial haplogroup T, as a means of identifying those [patients with] metastatic melanoma who are least likely to respond to immunotherapy treatment,” emphasized co–lead study author Kelsey Monson, PhD, an epidemiologist and a member of the Kirchhoff Laboratory at New York University (NYU) Langone Health.
Although both drug regimens proved effective in over 50% of all treated patients, the new analysis demonstrated that this positive treatment response declined to 18% in those with mitochondrial haplogroup T. To validate their findings, the researchers tested their initial results against samples from 675 patients of similar age and the same sex who had metastatic melanoma and received immune checkpoint inhibitors. The results confirmed the same link of immunotherapy resistance to mitochondrial haplogroup T.
Additionally, the researchers revealed that treatment-resistant patients with mitochondrial haplogroup T had more underdeveloped T cells in their blood compared with nonresistant patients without the haplogroup. The researchers traced this poor differentiation to increased resilience to reactive oxygen species—toxic chemicals primarily produced by mitochondria—suggesting that mitochondrial haplogroup T conferred some reactive oxygen species protection that stunted the T-cell attack against tumors.
Conclusions
“Our findings make possible the clinical testing for the presence of mitochondrial haplogroup T to determine nonresponding patients before they start immunotherapy, so other treatment combinations can be considered,” suggested co–lead study author Robert Ferguson, PhD, a molecular biologist and a member of the Kirchhoff Laboratory at NYU Langone Health. “This in turn could improve patient survival,” he highlighted.
“This research fundamentally changes our understanding of mitochondrial genetics in immune response biology and personalized cancer immunotherapy. It also suggests that variations in mitochondrial DNA could have impact beyond melanoma and apply to checkpoint treatments of other cancers,” stressed senior study author Tomas Kirchhoff, PhD, Associate Professor in the Department of Population Health at the NYU Grossman School of Medicine and a member of the Perlmutter Cancer Center. “These study results also raise the possibility that other mitochondrial haplogroup variants could influence which patients respond to other immune checkpoint therapies, allowing us to use this biomarker to personalize treatment prediction to a larger patient population,” he underscored.
The researchers hope that their findings could open new research avenues to determine the precise role played by mitochondrial genetics, reactive oxygen species metabolism, and antitumor T-cell immunity in cancer therapy. They plan to conduct a prospective clinical trial to assess whether non–mitochondrial haplogroup T patients may respond better to immunotherapy compared with patients with mitochondrial haplogroup T, as well as whether the results could apply to other mitochondrial haplogroups and cancer types.
Disclosure: The research in this study was funded by the National Institutes of Health, Melanoma Research Alliance, and Italian Ministry of Health Ricerca Corrente program. The CheckMate-067 trial was sponsored by Bristol Myers Squibb. For full disclosures of the study authors, visit nature.com.
