Researchers at the Princeton University Branch of the ludwig Institute for Cancer Research have uncovered new ways a vitamin A-derived molecule can interfere with the immune system’s ability to fight cancer. The molecule, known as all-trans retinoic acid, was found to weaken natural anti-cancer immune responses and, under certain conditions, reduce the effectiveness of a promising type of cancer vaccine.
Vitamin A metabolites, also called retinoids, have long sparked debate because of their mixed effects on health and disease. The new findings, described across two scientific papers, help clarify this long-standing controversy. They also led to the development of the first experimental drugs designed to shut down the cellular signaling pathway triggered by retinoic acid.
How Retinoic Acid Undermines Cancer Vaccines
One of the studies, published in Nature Immunology, was led by Ludwig Princeton researcher Yibin Kang and graduate student cao Fang. The team found that retinoic acid produced by dendritic cells (DCs), key immune cells responsible for activating immune defenses, can reprogram these cells in a way that promotes tolerance toward tumors.
This tolerance significantly reduces the effectiveness of dendritic cell vaccines, a type of immunotherapy designed to train the immune system to recognise and attack cancer. The researchers also described the creation and preclinical testing of a drug that blocks retinoic acid production in both cancer cells and DCs. The compound,KyA33,improved the performance of DC vaccines in animal studies and also showed potential as a stand-alone cancer immunotherapy.
A New Strategy to Block Retinoid Signaling
A second study, led by former Kang lab graduate student Mark Esposito and published in the journal iScience, focused on designing drugs that inhibit retinoic acid production and disable retinoid signaling altogether. although scientists have studied retinoids for more than a century, attempts to create drugs that safely block their signaling have repeatedly failed.
The approach described in this study combined computational modeling with large-scale drug screening. This strategy provided the framework used to develop KyA33, marking a major advance in targeting a pathway that had resisted drug development for decades.
Broad Implications for Cancer Immunotherapy
“Taken together, our findings reveal the broad influence retinoic acid has in attenuating vitally important immune responses to cancer,” said Kang. “In exploring this phenomenon,we also solved a longstanding challenge in pharmacology by developing safe and selective inhibitors of retinoic acid signaling and established preclinical proof of concept for their use in cancer immunotherapy.”
A Deadly Form of Immune Tolerance
retinoic acid is produced by an enzyme called ALDH1a3, which is often found at high levels in human cancer cells. A related enzyme, ALDH1a2, produces retinoic acid in certain subsets of DCs.
Once generated, retinoic acid activates a receptor inside the cell nucleus, launching a signaling cascade that changes gene activity. In the gut, this process is known to promote the formation of regulatory T cells (Tregs), which help prevent harmful autoimmune reactions. Until now, though, scientists did not understand how retinoic acid affects dendritic cells themselves.
Why Dendritic Cells Matter in Cancer Defense
Dendritic cells play a central role in coordinating immune responses. They continuously survey the body for signs of infection or cancer. When they detect danger, they process fragments of abnormal proteins and present them as antigens to T cells, which then seek out and destroy diseased or cancerous cells.
Dendritic cell vaccines are created by collecting immature immune cells from a patient’s blood and growing them in the laboratory alongside antigens taken from that patient’s tumor. These primed cells are then returned to the patient with the goal of triggering a powerful anti-tumor immune response.
Despite improvements in identifying suitable cancer antigens, these vaccines frequently enough fail to perform as hoped. Fang,Kang,and their colleagues,including Esposito and Princeton Branch Director Joshua Rabinowitz,set out to understand why.
How Vaccine Production Triggers Immune Suppression
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Summary of the Research on ALDH1A Inhibitors & Cancer
This article details groundbreaking research into the role of ALDH1A enzymes (specifically ALDH1a2 and ALDH1a3) in cancer development and a potential new immunotherapy approach. Here’s a breakdown of the key findings:
1. KyA33 & Restoring Immune Function:
* A new drug, KyA33, blocks ALDH1a2 and restores the function of dendritic cells (DCs). DCs are crucial for activating the immune system against cancer.
* KyA33 enhanced the effectiveness of DC vaccines in mouse models of melanoma, delaying tumor growth and slowing progression.
* KyA33 itself also acted as an immunotherapy when directly administered to mice, reducing tumor growth by stimulating the immune system.
2.Solving the Vitamin A paradox:
* The research successfully targeted the retinoic acid pathway, a previously “untargetable” signaling pathway.
* This breakthrough explains why vitamin A has seemingly contradictory effects on cancer: while retinoic acid can inhibit cancer cell growth in vitro, high vitamin A intake is linked to increased cancer risk in vivo.
* Cancer cells overexpress ALDH1a3 to produce retinoic acid, but simultaneously become resistant to its effects.
3. How Cancer Exploits Retinoic acid:
* Retinoic acid doesn’t directly kill cancer cells; instead, it suppresses the immune response around the tumor, hindering T cell activity.
* Inhibiting ALDH1a3 boosts immune attacks on tumors in mouse models.
4. Future Implications:
* Researchers have formed a biotechnology company, Kayothera, to develop ALDH1A inhibitors for clinical trials.
* These inhibitors have potential for treating not only cancer but also other diseases influenced by retinoic acid, such as diabetes and cardiovascular disease.
5. Funding:
* The research was supported by numerous organizations including the Ludwig Institute for Cancer Research, Susan Komen Foundation, and the National Science Foundation.
In essence, this research identifies a key mechanism by which cancer evades the immune system and proposes a novel therapeutic strategy to overcome this evasion by targeting ALDH1A enzymes.
