Scientists have revealed a previously unknown immune pathway that cancerous tumors exploit to evade the immune system, and it depends on a derivative of… Vitamin A . Research has shown that selectively disrupting this pathway reactivates the immune response and improves treatment outcomes in experimental models of cancer.
How does a derivative of vitamin A suppress anti-cancer immunity?
Table of Contents
- How does a derivative of vitamin A suppress anti-cancer immunity?
- Old scientific controversy in your new book
- The first study: inactivation of dendritic cell vaccines
- Study 2: Silencing intracellular retinoid signaling
- Broad effect on the immune response
- The role of ALDH1A enzymes in promoting immune tolerance
- Why do dendritic cell vaccines often fail?
- Disabling the pathway restores immune effectiveness
- Solving the vitamin A and cancer paradox
- The tumor does not respond, but it deactivates the immune system
- Targeting the environment surrounding the tumor
- A step towards clinical application
Researchers at the Princeton branch of the Ludwig Institute for Cancer Research have identified new mechanisms by which a compound derived from vitamin A, known as all-trans retinoic acid, impairs the immune system’s ability to fight cancer.
The results showed that this compound not only weakens natural anti-tumor immunity, but may also reduce the effectiveness of a promising class of cancer vaccines in certain circumstances.
Old scientific controversy in your new book
Vitamin A derivatives, known as retinoids, have long been the subject of widespread medical controversy, with previous studies showing both positive and negative effects.
The results of these two studies, published separately, helped clarify this decades-long scientific contradiction and represent an important step towards developing the first drugs capable of disrupting the cellular signaling pathway activated by retinoic acid.
The first study: inactivation of dendritic cell vaccines
The first study, published in the journal Nature Immunology, was led by researcher Yi Bin Kang and graduate student Cao Fang.
It focused on retinoic acid, which is produced by dendritic cells within the immune system, as it was shown that this compound:
Changes the behavior of dendritic cells
Promotes a state of “immune tolerance” towards tumors
Weaken immune responses targeting cancer cells
Direct effect on cancer vaccines
This immune tolerance undermines the effectiveness of dendritic cell vaccines, a type of immunotherapy aimed at stimulating a strong anti-tumor response.
The researchers also described the development and testing of a new drug compound known as KyA33, which works to block retinoic acid production in both cancer cells and dendritic cells.
Pre-clinical trials showed that:
KyA33 significantly improved the efficacy of dendritic cell vaccines
It may also work as a stand-alone immunotherapy
Study 2: Silencing intracellular retinoid signaling
The second study, published in the journal iScience, was led by researcher Mark Esposito, and focused on designing and testing drugs that block the production of retinoic acid, thus effectively stopping retinoid signaling within cells.
Although retinoids have been studied for more than 100 years, all previous attempts to develop safe and effective drugs to disrupt this pathway have failed, until this study succeeded in overcoming those obstacles.
Broad effect on the immune response
Researcher Yi Bin Kang says:
“Our results reveal the broad influence of retinoic acid in dampening critical immune responses against cancer, and we have solved a long-standing pharmacological problem by developing safe and selective inhibitors of this pathway.”
The role of ALDH1A enzymes in promoting immune tolerance
Retinoic acid is produced by an enzyme called ALDH1A3, which is found at high levels in many human cancer cells. A related enzyme, ALDH1A2, also produces the same compound within certain types of dendritic cells.
After its production, retinoic acid binds to receptors within the cell nucleus, causing a series of changes in gene expression.
Why do dendritic cell vaccines often fail?
Dendritic cell vaccines are manufactured by:
Collecting immature immune cells from the patient’s blood
Exposing it to antigens extracted from the tumor
Return it to the body to stimulate immunity
But clinical results were often disappointing.
The researchers explain that the reason is that dendritic cells, during their preparation in the laboratory, begin to produce retinoic acid in large quantities, which:
It prevents its natural maturation
Reduces its ability to activate anti-cancer immunity
Disabling the pathway restores immune effectiveness
Researchers have demonstrated that inactivating the ALDH1A2 enzyme, either genetically or using KyA33, restores:
Normal development of dendritic cells
Its ability to stimulate a strong immune response
In mouse models of skin cancer (melanoma), this response led to:
Delaying the growth of tumors
Slowing the progression of the disease
When given directly as an immunotherapy, KyA33 was also successful in reducing tumor growth.
Solving the vitamin A and cancer paradox
Retinoic acid has long been considered an anti-cancer agent in laboratory experiments, showing an ability to stop the growth of cancer cells.
However, major clinical studies have shown that:
Excessive intake of vitamin A
It is associated with increased cancer rates
High mortality and heart disease are associated with it
This study clarifies the biological basis for this discrepancy.
The tumor does not respond, but it deactivates the immune system
Researcher Mark Esposito explained:
“Cancer cells produce retinoic acid, but lose their ability to respond to its signals, evading its growth-inhibiting effect, while using it to suppress immunity in the environment surrounding the tumor.”
Thus, retinoic acid is used as a weapon against the immune system rather than the cancer cells themselves.
Targeting the environment surrounding the tumor
Researchers have demonstrated that new ALDH1A3 inhibitors:
Stimulates the immune system to attack tumors
It acts as an effective immunotherapy in animal models
Kang asserts:
“We are paving the way for a new therapeutic approach that safely and precisely targets the retinoic acid pathway.”
A step towards clinical application
Kang and Esposito founded a biotech company, Kayothera, with the goal of taking these new inhibitors into clinical trials to treat multiple retinoic acid-related diseases, including:
Cancer
Diabetes
Cardiovascular diseases.
