Researchers have discovered that a byproduct of vitamin A, all-trans retinoic acid, weakens the immune system's fight against cancer and reduces the effectiveness of certain vaccines. In preclinical studies, a new drug called KyA33 blocks this pathway, enhancing immune responses and slowing tumor growth. The findings, from two studies, explain a long-standing paradox about vitamin A's role in cancer.
Scientists at the Princeton University Branch of the Ludwig Institute for Cancer Research have revealed how all-trans retinoic acid, a vitamin A metabolite, interferes with anti-cancer immunity. This molecule, produced by enzymes ALDH1a3 in cancer cells and ALDH1a2 in dendritic cells, promotes immune tolerance toward tumors. Dendritic cells, which activate immune defenses by presenting tumor antigens to T cells, become reprogrammed by retinoic acid, suppressing their maturation and anti-tumor activity.
One study, published in Nature Immunology and led by Yibin Kang and Cao Fang, examined dendritic cell vaccines, an immunotherapy that trains the immune system against cancer. The researchers found that during vaccine production, dendritic cells express ALDH1a2, generating high levels of retinoic acid that hinder their function. "We discovered that under conditions commonly employed to produce DC vaccines, differentiating dendritic cells begin expressing ALDH1a2, producing high levels of retinoic acid," said Fang. "The nuclear signaling pathway it activates then suppresses DC maturation, diminishing the ability of these cells to trigger anti-tumor immunity."
This mechanism also fosters less effective macrophages, further weakening vaccine performance. To counter it, the team developed KyA33, which inhibits retinoic acid production. In mouse models of melanoma, KyA33-enhanced vaccines delayed tumor development, and the drug alone stimulated immune attacks on tumors.
A companion study in iScience, led by Mark Esposito, used computational modeling and drug screening to create inhibitors targeting the retinoic acid pathway, long resistant to drug development. "Our study reveals the mechanistic basis for this paradox," Esposito noted, explaining how cancer cells exploit retinoic acid to suppress surrounding immune responses while avoiding its direct anti-proliferative effects.
The discoveries resolve why high vitamin A intake links to increased cancer risk despite lab evidence of its benefits. Kang highlighted the implications: "Taken together, our findings reveal the broad influence retinoic acid has in attenuating vitally important immune responses to cancer." Esposito and Kang have founded Kayothera to advance these inhibitors toward clinical trials for cancer, diabetes, and cardiovascular disease.
