Vitamin A Byproduct Lets Cancer Evade Immune System

Researchers at Princeton have found that a byproduct of vitamin A helps cancer cells hide from the body's defenses. This molecule, called all-trans retinoic acid, weakens immune cells and makes cancer vaccines less effective. In lab tests with mice, a new drug blocked this process and slowed tumor growth.

Background

Vitamin A is in many foods like carrots, sweet potatoes, and liver. The body turns it into retinoic acid to help with vision, growth, and immune function. For years, people thought extra vitamin A might fight cancer. Lab tests showed it could slow cancer cell growth or make them mature normally.

But real-world data told a different story. Large studies found that people taking high doses of vitamin A had higher risks of cancer and heart problems. They also died sooner in some cases. Tumors often had high levels of enzymes that make retinoic acid, and that linked to worse outcomes for patients.

This created a puzzle. Why did vitamin A look good in dishes but bad in bodies? Scientists at the Ludwig Institute for Cancer Research in Princeton dug into it. They looked at how retinoic acid acts not just on cancer cells, but on the immune cells around tumors.

Dendritic cells are key players in the immune system. They spot trouble like cancer and alert T cells to attack. But these cells can make retinoic acid themselves. That sends a signal telling the immune system to stand down, like a false flag of safety.

Cancer cells do the same trick. They pump out retinoic acid through enzymes called ALDH1a2 and ALDH1a3. This floods the area around the tumor, calming immune responses. T cells, which should kill cancer, get quieted instead.

Key Details

The Princeton team ran tests on mice with melanoma, a skin cancer. They saw retinoic acid from dendritic cells cut the power of cancer vaccines. These vaccines use lab-grown dendritic cells to train the immune system against tumors. But retinoic acid made those cells promote tolerance instead of attack.

To fix this, researchers screened thousands of drugs. They used computer models to find ones that hit ALDH1a2 and ALDH1a3 without side effects. They landed on KyA33, a compound that stops retinoic acid production in both cancer cells and dendritic cells.

In one set of tests, mice got dendritic cell vaccines made with KyA33. Tumors grew slower, and immune responses were stronger. T cells ramped up and targeted the cancer better.

KyA33 worked alone too. Given straight to mice with tumors, it shrank them by waking up the immune system. No vaccines needed. The drug hit tumors across different types in the models.

How the Drug Was Made

Making drugs against retinoic acid was tough. This pathway was found first among cell signals, but no one cracked safe blockers for it. Past tries failed because they hit other body functions. The Princeton method mixed math models with big drug hunts. It zeroed in on the enzymes without messing up vision or growth.

"Taken together, our findings reveal the broad influence retinoic acid has in attenuating vitally important immune responses to cancer," said Yibin Kang, a researcher who led the study. "In exploring this phenomenon, we also solved a longstanding challenge in pharmacology by developing safe and selective inhibitors."

Another team member, Cao Fang, pointed to vaccine making. During the process to grow dendritic cells for shots, they start making lots of retinoic acid. That stalls their growth and weakens the final product.

"We discovered that under conditions commonly employed to produce DC vaccines, differentiating dendritic cells begin expressing ALDH1a2, producing high levels of retinoic acid," Fang said. "This previously unknown mechanism likely contributes to the largely suboptimal performance of DC and other cancer vaccines."

A third expert, Michela Esposito, explained the cancer side. Tumors overproduce the enzyme ALDH1a3 to make retinoic acid. But cancer cells ignore its stop-growth signal. They use it to hush the immune neighborhood instead.

What This Means

This work explains why cancer vaccines often fall short in people. Many trials showed weak results. Retinoic acid from the process or tumors likely played a part. Blocking it with KyA33 could make those vaccines work better.

The drug also stands alone. It boosts natural immune attacks without extra steps. In mice, it slowed tumors that normally resist treatment. That opens doors for hard-to-treat cancers.

Retinoic acid mainly hits the space around tumors, not the cells direct. It quiets T cells and other fighters. Drugs like KyA33 could pair with checkpoint blockers, which already help some patients. Together, they might hit more cancer types.

High vitamin A links to worse survival in many cancers. Tumors with lots of these enzymes mean poor odds. This ties it to immune escape, not just cell growth.

The findings change views on vitamin A supplements. People take them for health, but extra might feed cancer hiding. Doctors may test ALDH levels in tumors to pick patients for KyA33.

Next steps mean human trials. The mouse success sets up tests for safety and effect. If it holds, it could add to immunotherapy tools. Cancer care often mixes drugs now. KyA33 fits that pattern.

Other research shows retinoic acid with radiation can help in some cases. It turns bad immune cells good there. But this new view shows its main role aids tumor escape. Context matters.

Patients with high ALDH in scans might benefit most. It flags tumors using this trick. Tools to measure retinoic acid in blood or tissue could guide use.

This builds on years of work. The vitamin A paradox lasted decades. Now, with KyA33, there's a path forward. Labs worldwide may test it against breast, lung, and other common cancers seen in the mouse work.