Vitamin A & Cancer: Immune System Interference?

Vitamin A Molecule Undermines Cancer Immunity, New Drugs Offer Hope

A vitamin A-derived molecule, all-trans retinoic acid, can significantly weaken the immune system’s ability to fight cancer and reduce the effectiveness of promising cancer vaccines, according to groundbreaking research from Princeton University. The findings, published in two studies, reveal a complex role for this molecule and pave the way for novel immunotherapies targeting a previously intractable pathway.

The Paradox of Vitamin A and Cancer

For decades, the impact of vitamin A, and its metabolites known as retinoids, on health and disease has been a subject of intense debate. While lab studies have suggested anti-cancer properties, large-scale clinical trials have paradoxically linked high vitamin A intake to increased cancer risk and mortality. Researchers at the Ludwig Institute for Cancer Research have now begun to unravel this mystery, identifying how retinoic acid can actively suppress the immune response against tumors.

How Retinoic Acid Hijacks Immune Cells

The research team, led by Yibin Kang and graduate student Cao Fang, discovered that retinoic acid produced by dendritic cells (DCs) – crucial immune cells responsible for activating anti-cancer defenses – can reprogram these cells to tolerate tumors. This tolerance dramatically diminishes the effectiveness of dendritic cell vaccines, a type of immunotherapy designed to train the immune system to recognize and destroy cancer cells.

“Our findings reveal the broad influence retinoic acid has in attenuating vitally important immune responses to cancer,” Kang stated.

The team also developed and pre-clinically tested a compound, KyA33, that blocks retinoic acid production in both cancer cells and DCs. In animal studies, KyA33 significantly improved the performance of DC vaccines and demonstrated potential as a standalone cancer immunotherapy.

A New Approach to Blocking Retinoid Signaling

A parallel study, led by former Kang lab graduate student Mark Esposito, focused on designing drugs to completely disable retinoic acid signaling. Despite over a century of research on retinoids, creating drugs to safely block their signaling had proven elusive.

The researchers employed a novel strategy combining computational modeling with large-scale drug screening, ultimately leading to the development of KyA33. This breakthrough represents a major advance in targeting a pathway that had resisted drug development for decades.

The Role of ALDH1a Enzymes

Retinoic acid is produced by enzymes called ALDH1a3, often found in high concentrations in cancer cells, and ALDH1a2, present in certain subsets of DCs. Once formed, retinoic acid activates a receptor within the cell nucleus, triggering a signaling cascade that alters gene activity. While this process is known to promote the formation of regulatory T cells (Tregs) in the gut – helping to prevent autoimmune reactions – its impact on DCs was previously unknown.

Why Dendritic Cells Are Key to Cancer Defense

Dendritic cells are central to coordinating immune responses. They constantly monitor the body for signs of infection or cancer, processing fragments of abnormal proteins and presenting them as antigens to T cells, which then seek out and destroy diseased cells.

Dendritic cell vaccines are created by priming a patient’s own immune cells with tumor-specific antigens, aiming to trigger a powerful anti-tumor immune response. However, these vaccines often underperform, prompting Kang, Fang, Esposito, and their colleagues to investigate the underlying reasons.

How Vaccine Production Can Backfire

“We discovered that under conditions commonly employed to produce DC vaccines, differentiating dendritic cells begin expressing ALDH1a2, producing high levels of retinoic acid,” explained Fang. “The resulting signaling pathway suppresses DC maturation, diminishing their ability to trigger anti-tumor immunity. This previously unknown mechanism likely contributes to the suboptimal performance of DC and other cancer vaccines seen in clinical trials.”

The problem extends beyond DC maturation. Retinoic acid released by DCs also encourages the formation of less effective macrophages, further hindering the vaccine’s impact.

Restoring Immune Power with KyA33

The researchers demonstrated that blocking ALDH1a2, using either genetic techniques or KyA33, restores DC maturation and their ability to activate immune defenses. DC vaccines created with KyA33 generated strong, targeted immune responses in mouse models of melanoma, delaying tumor development and slowing progression.

Administered directly to mice, KyA33 also functioned as an independent immunotherapy, reducing tumor growth by stimulating the immune system.

Solving the Vitamin A Paradox: Cancer’s Clever Strategy

Developing inhibitors targeting ALDH1a2 and ALDH1a3 is a significant scientific achievement, as the retinoic acid pathway was the first nuclear receptor signaling pathway discovered, yet remained resistant to drug targeting for decades.

The iScience study details the computational and experimental approach used to overcome this challenge, finally explaining the long-standing paradox surrounding vitamin A and cancer. While retinoic acid can inhibit cancer cell growth in the lab, clinical trials show high vitamin A intake increases cancer risk.

“Our study reveals the mechanistic basis for this paradox,” said Esposito. “Cancer cells overexpress ALDH1a3 to generate retinoic acid, but lose their responsiveness to retinoid receptor signaling, avoiding its potential anti-proliferative effects.”

The research also revealed that retinoic acid primarily affects the immune environment around tumors, suppressing immune responses, including T cell activity. Inhibiting ALDH1a3 stimulated strong immune attacks against tumors in mouse models, demonstrating the potential of these inhibitors as powerful immunotherapies.

A New Era for Cancer Immunotherapy and Beyond

“By developing candidate drugs that safely and specifically inhibit nuclear signaling through the retinoic acid pathway, we are paving the way for a novel therapeutic approach to cancer,” Kang concluded.

Esposito and Kang have launched Kayothera, a biotechnology company, to advance these ALDH1A inhibitors into clinical testing, with plans to develop treatments for cancer, diabetes, and cardiovascular disease. .

The Nature Immunology study was supported by the Ludwig Institute for Cancer Research, the Brewster Foundation, the Susan Komen Foundation, Metavivor Breast Cancer Research, the Breast Cancer Research Foundation, and the American Cancer Society. The iScience study received support from the Ludwig Institute for Cancer Research, the New Jersey Health Foundation, the Brewster Foundation, the Susan Komen Foundation, the Breast Cancer Research Foundation, the American Cancer Society, and the National Science Foundation. Yibin Kang is a member of the Princeton Branch of the Ludwig Institute for Cancer Research, the Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University, and an Associate Director of Rutgers Cancer Institute of New Jersey.