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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Thursday, January 2, 2025
Ana P. Gomes, PhD, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and colleagues hypothesized that increased levels of methylmalonic acid (a small molecule that plays a big role in breaking down proteins in the body) may promote tumor progression, but their role in modulating the tumor ecosystem remains unknown. The investigators’ study, which was published in the journal Oncogene, aimed to evaluate precisely how methylmalonic acid inhibits CD8-positive T cells from attacking lung carcinoma.
“Our research shows that methylmalonic acid not only increases with age but also makes CD8-positive T cells weaker by disrupting their energy production,” stated Dr. Gomes in an institutional press release. “This makes it harder for the immune system to fight cancer, suggesting that targeting methylmalonic acid could help improve cancer treatment.”
The researchers obtained male and female C57BL/6NJ mice for this study. Mice were divided into two groups, either treated with saline or methylmalonic acid by injection twice daily, with 8 hours between doses, for 28 days. Doses of methylmalonic acid were gradually increased to 0.76, 1.01, 1.86, and 2.67 μmol/g of body weight at weeks 1, 2, 3, and 4, respectively. On day 4, mice were injected with tumor cells at 100,000 cells/100 μL phosphate-buffered saline; mice were euthanized on day 28, and their spleen and lung tissues were collected for analysis.
Treatment with methylmalonic acid appeared to upregulate CD8-positive T-cell exhaustion markers, thereby decreasing their effector functions and leading to antitumor immunity suppression. Further, treating primary CD8-positive T cells with methylmalonic acid yielded a dysfunctional phenotype, causing marked increases in the expression of TOX—an exhaustion regulator—as well as immunosuppressive transcriptional reprogramming.
To induce CD8-positive T-cell exhaustion, methylmalonic acid appeared to suppress NADPH-regenerating reactions in the tricyclic acid cycle, as well as render mitochondrial function defective. Methylmalonic acid ultimately plays an immunomodulatory role in the tumor microenvironment, shedding light on its link in the triad of cancer, aging, and immune dysfunction.
Disclosure: The study authors reported no conflicts of interest.
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