Researchers at Princeton University’s Ludwig Institute for Cancer Research have discovered new ways in which vitamin A-derived molecules can interfere with the immune system’s ability to fight cancer. The molecule, known as all-trans retinoic acid, was found to impair natural anti-cancer immune responses and, under certain conditions, reduce the effectiveness of a promising cancer vaccine.
Vitamin A metabolites, also known as retinoids, have long been controversial because of their mixed effects on health and disease. New findings described in two scientific papers help clarify this long-standing debate. It also led to the development of the first experimental drug designed to block cell signaling pathways triggered by retinoic acid.
How retinoic acid sabotages cancer vaccines
A study published in natural immunologyled by Ludwig Princeton University researcher Kang Yibin and graduate student Cao Fang. The team found that the retinoic acid produced by dendritic cells (DCs), the main immune cells responsible for activating immune defenses, can reprogram these cells to enhance their ability to tolerate tumors.
This tolerance significantly reduces the effectiveness of stem cell vaccines, a type of immunotherapy designed to train the immune system to recognize and attack cancer. The researchers also describe the creation and preclinical testing of a drug that blocks the production of retinoic acid by cancer cells and stem cells. The compound, KyA33, improved the performance of DC vaccines in animal studies and also showed potential for use as a standalone cancer immunotherapy.
New strategies to inhibit retinoid signaling
A second study, led by Mark Esposito, a former graduate student in Kang’s lab, is published in the journal scienceHe focuses on designing drugs that inhibit retinoic acid production and completely inactivate retinoic acid signaling. Although scientists have been studying retinoids for more than a century, attempts to create drugs that safely block their signals have repeatedly failed.
The method described in this study combines computational modeling and large-scale drug screening. This strategy provides a framework for the development of KyA33 and represents a significant advance against a pathway that has hindered drug development for decades.
The broad impact of cancer immunotherapy
“Taken together, our findings reveal the broad impact of retinoic acid in attenuating immune responses, which are critical to cancer,” Kang said. “In exploring this phenomenon, we also address a long-standing challenge in pharmacology through the development of safe and selective inhibitors of retinoic acid signaling and preclinical proof-of-concept for their use in cancer immunotherapy.”
fatal immune tolerance
Retinoic acid is produced by an enzyme called ALDH1a3, which is found in high concentrations in human cancer cells. A related enzyme, ALDH1a2, produces retinoic acid in certain DC subsets.
Once produced, retinoic acid activates receptors in the cell nucleus, triggering a cascade of signals that alter gene activity. In the gut, this process promotes the formation of regulatory T cells (Tregs), which help prevent harmful autoimmune reactions. But until now, scientists didn’t understand how retinoic acid affects the stem cells themselves.
Why stem cells are important in cancer defense
Stem cells play a central role in orchestrating immune responses. They constantly scan the body for signs of infection or cancer. When they detect danger, they process fragments of the abnormal protein and present them as antigens to T cells, which then seek out and destroy diseased or cancerous cells.
Stem cell vaccines are made by collecting immature immune cells from a patient’s blood and growing them in the laboratory along with antigens extracted from the patient’s tumor. These prepared cells are then infused back into the patient, with the goal of triggering a strong anti-tumor immune response.
Despite advances in identifying appropriate cancer antigens, these vaccines often fail to achieve the desired results. Fang, Kang and their colleagues, including Esposito and Princeton chapter director Joshua Rabinowitz, set out to understand why.
How does vaccine production lead to immunosuppression?
“We found that under conditions typically used to produce DC vaccines, differentiated dendritic cells begin to express ALDH1a2 and produce high levels of retinoic acid,” said Fang. “The nuclear signaling pathways it activates subsequently inhibit DC maturation, thereby reducing the ability of these cells to stimulate anti-tumor immunity. This previously unknown mechanism may contribute to the largely suboptimal performance of DCs and other cancer vaccines that repeatedly appear in clinical trials.”
The problem doesn’t stop there. Retinoic acid released by dendritic cells also promotes the formation of less effective cancer-fighting macrophages. As these macrophages accumulate instead of functional stem cells, the overall effectiveness of stem cell vaccines decreases further.
Restoring immunity with new drugs
The researchers demonstrated that blocking ALDH1a2, either through genetic techniques or using KyA33, restored stem cell maturation and their ability to activate immune defenses. DC vaccines generated in the presence of KyA33 generated robust and targeted immune responses in a mouse model of melanoma. These responses delay tumor development and slow cancer progression.
When given directly to mice, KyA33 also acted as a stand-alone immunotherapy, reducing tumor growth by stimulating the immune system.
Solving the Vitamin A Cancer Paradox
The development of inhibitors targeting ALDH1a2 and ALDH1a3 represents a major scientific breakthrough. Among the twelve classic nuclear receptor signaling pathways, the retinoic acid pathway was the first to be discovered, and it is also the only pathway that has not yet been successfully targeted by drugs.
this science This study details the computational and experimental methods used to overcome this challenge. Thanks to these new compounds, researchers are finally able to explain the long-standing paradox surrounding vitamin A and cancer.
In laboratory experiments, retinoic acid can cause cancer cells to stop growing or die, leading to belief that vitamin A has anti-cancer properties. However, large clinical trials and other evidence suggest that high intakes of vitamin A increase the risk of cancer (and cardiovascular disease) and increase mortality. High levels of the ALDH1A enzyme in tumors are also associated with poor survival in many cancers. Previous attempts to separate the function of the ALDH1A enzyme from retinoic acid production have been largely unsuccessful.
How cancer uses retinoic acid
“Our study reveals the mechanistic basis of this paradox,” Esposito said. “We have shown that ALDH1a3 is overexpressed in various types of cancer to produce retinoic acid, but the cancer cells lose their response to retinoid receptor signaling, thereby avoiding its potential anti-proliferative or anti-differentiation effects. This partly explains the paradox of vitamin A’s effect on cancer growth.”
The researchers also found that retinoic acid primarily affected the immune environment surrounding tumors rather than the cancer cells themselves. By entering the tumor microenvironment, retinoic acid suppresses immune responses, including the activity of T cells that normally target cancer.
To confirm this, the team demonstrated that ALDH1a3 inhibitors induced a strong immune attack against tumors in mouse models, demonstrating their potential as powerful immunotherapies.
Finding new treatments for cancer and other diseases
“By developing drug candidates that safely and specifically inhibit nuclear signaling through the retinoic acid pathway, we are paving the way for new treatments for cancer,” Kang said.
Esposito and Kang have since formed a biotech company, Kyuthera, to develop these ALDH1A inhibitors into clinical testing. The company aims to develop treatments for a variety of diseases affected by retinoic acid, including cancer, diabetes and cardiovascular disease.
Funding and research support
this natural immunology The research was supported by the Ludwig Cancer Institute, the Brewster Foundation, the Susan G. Komen Foundation, MetaVivor Breast Cancer Research, the Breast Cancer Research Foundation and the American Cancer Society.
this science The research was supported by the Ludwig Cancer Institute, 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 Ludwig Institute for Cancer Research in Princeton, the Warner-Lambert/Parker-Davis Professor of Molecular Biology at Princeton University, and the deputy director of the Rutgers Cancer Institute of New Jersey.
