Moffitt Cancer Center researchers have found new insights into how metabolic changes associated with aging can impact immune responses against tumors. Their study, published in Oncogene, explores how increased methylmalonic acid impairs the activation and effector functions of CD8+ T cells, immune cells that play a vital role in fighting cancer.

Methylmalonic acid levels are normally low in healthy individuals. Elevated levels have been linked to aging and vitamin B12 deficiency, raising questions about their role in cancer biology.

“Our research shows that methylmalonic acid not only increases with age but also makes CD8+ T cells weaker by disrupting their energy production,” said Ana Gomes, Ph.D., lead author on the study and principal investigator in the Molecular Oncology Department at Moffitt. “This makes it harder for the immune system to fight cancer, suggesting that targeting methylmalonic acid could help improve cancer treatment.”

Researchers found that methylmalonic acid treatment significantly reduced the activity of CD8+ T cells, an important component of the immune response to tumors. The study’s results indicate that methylmalonic acid influences global gene expression in these cells, leading to the downregulation of key pathways involved in immune activation and metabolism.

The study also highlights the role of methylmalonic acid in skewing the tumor microenvironment, affecting not only T cells but also other immune cells, potentially contributing to a more favorable environment for tumor growth and metastasis.

These findings suggest that strategies aimed at reducing methylmalonic acid levels or counteracting its effects on CD8+ T cells could enhance antitumor immunity, particularly in older patients who are at greater risk for lung cancer.

This study was supported by the National Institutes of Health (P30 CA076292, P30 CA006516, T32 CA233399, P01 CA250984, P01 CA250984, P01 CA120964, R00 CA218686, R00 CA218686‐04S1, DP2AG0776980, R01 CA279023, R21 AG083720), the American Cancer Society (RSG-22-164-01-MM), the Florida Health Department Bankhead-Coley Research Program (24B03), METAvivor, the Florida Breast Cancer Research Foundation and the Phi Beta Psi Sorority.

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A study by Moffitt Cancer Center researchers reveals that metabolic changes linked to aging, specifically increased methylmalonic acid, impair CD8+ T cell function, crucial for cancer defense. Elevated methylmalonic acid, associated with aging and vitamin B12 deficiency, disrupts energy production in these cells, weakening immune responses against tumors. The research indicates that methylmalonic acid alters gene expression, affecting immune activation and metabolism, and skews the tumor microenvironment. Targeting methylmalonic acid could enhance antitumor immunity, especially in older patients at higher risk for lung cancer.

A new study has found a surprising link between high levels of methylmalonic acid and the weakening of CD8+ T cells, shedding light on potential pathways through which aging may promote lung cancer progression.

Moffitt Cancer Center

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Moffitt Study Links Methylmalonic Acid to Weakening of Immune Cells in Lung Cancer