Everything we know about the way brain tumours in children and young people start suggests that boosting the body’s own defences (the immune system) should be an effective way of stopping them.

Most of these cancers begin developing before a baby is born, and before the immune system has the tools it needs to identify them as threats. Even once the immune system is established, it’s at a disadvantage – cancer cells in children and young people can look and act a lot like the healthy cells that are growing all around them.

That’s supposed to be where immunotherapies come in. These treatments are designed to show the immune system how to find hidden tumour cells, so they should be powerful tools for stopping young patients’ brain tumours in their tracks. But the brain isn’t like any other part of the body, and for years, researchers couldn’t find a reliable way to make immunotherapies work there.

Then their understanding of the brain began to change.

First, scientists in the US uncovered that, despite their apparent differences, the brain and the immune system are constantly communicating. And now, Dr Elizabeth Cooper and her team at the Cancer Research UK Cambridge Institute have found a way to tap into that communication system with a treatment. Thanks to their discovery, immunotherapy may finally be able to fulfil its promise for children and young people with brain tumours.

The brain’s hidden connection to the immune system

The story starts in 2022, when researchers at the Washington University School of Medicine in the US made a breakthrough in understanding how the brain protects itself from infection. 

That’s relevant because, although infections are very different from cancer, the immune system guards against both. It does that by growing disease-fighting cells in the soft centre of bones (called marrow) and transporting them through a network of tubes called the lymphatic system. The lymphatic system can then work with the bloodstream to deliver immune cells where they’re needed.

Crucially, though, the lymphatic system doesn’t extend into the brain, and the brain’s blood vessels are too tightly sealed to let any immune cells through that way, either. Because of this, scientists had long thought that the brain was cut off from the immune system, almost as if it were in a separate protective bubble.

The team at Washington University proved otherwise. They discovered that the brain had been communicating with the immune system all along. And it was doing it through the bubble itself – a liquid that surrounds the brain called cerebrospinal fluid (CSF). 

“Cerebrospinal fluid was always thought of as this cushioning fluid that keeps the brain floating, but it’s actually a communication method,” says Cooper, who studies children’s brain tumours as part of the Gilbertson Group in Cambridge.

Like a courier, CSF carries messages between the brain and immune cells in the marrow of the skull.

“The brain uses CSF to talk to immune cells, much like the blood [in other parts of the body]. It can tell cells in the CSF what to do and even use them as a way of patrolling for anything wrong.”

The important immune cells here are known as immune stem cells – multipurpose immune cells that can produce other more specialised ones to do different jobs. The team in the US showed that the skull’s immune stem cells can sense proteins and molecules from the brain through the CSF. When they notice proteins from intruders like infections, they produce new cells that can launch an immune attack. 

All that got Cooper thinking: if the immune system can respond to signals sent by infections in the brain, can it also respond to signals from tumours? 

Hijacking the immune system

To try and answer that question, Cooper and her team looked at mice with the three types of brain tumour most commonly found in children and young people: ependymoma, medulloblastoma and choroid plexus carcinoma. It didn’t take long for them to spot signs that tumour cells can release their own signals into the CSF.

Unlike signals from infected cells, which guide the immune system, these tumour signals are sent to trick it. They hijack the receptors on immune stem cells and push them to produce cells called myeloid cells, which hold the rest of the immune system back from attacking. In effect, the tumour uses the immune cells in the CSF to reprogramme its environment so it can grow unchecked.

Cooper’s team first saw his happening in ependymomas, but, as they kept researching, they found that all three tumour types actually use the same mechanism.

That makes their discovery even more important. Many of today’s immunotherapies can only be offered to a small subset of people with specific features on their cancer cells. Others are only suitable for certain cancer types and need to be personalised before they can be used at all. This finding pointed to something different. If multiple childhood brain tumours communicate in the same way, it could be possible to target them all with a single immunotherapy.

But for that kind of universal treatment to become a reality, the team needed to find a way of interrupting the communication loop. They tested two different methods: stopping the signals before they reach the immune stem cell receptors and blocking the immune stem cell receptors so they don’t interact with the signals. The second of those approaches stood out.

A single interruption

Cooper gave the mice a dose of proteins called antibodies designed to latch onto and defend the receptors the tumours were targeting with their signals. That was all it took for something dramatic to happen. From that point on, the mice’s immune systems could recognise and attack the tumours, causing them to shrink and helping the mice live longer.

“It was pretty profound to see such a strong effect from just one dose,” Cooper says. “For children, daily treatments are incredibly burdensome, so the idea that you could rewire the tumour environment by altering just one key interaction is really exciting. It shows how powerful the immune system is when you can nudge it in the right direction.”

Although it’s unlikely one dose could be sufficient in humans, the idea of rewiring the tumour environment is still powerful. The chemotherapy and radiotherapy options doctors have for treating children’s and young people’s brain tumours today need to be used repeatedly, which contributes to their risk of causing severe long-term side effects. The Gilbertson Group’s discovery could pave the way for treatments that help more children and young people recover without leaving the same marks.

“We’ve shown one mechanism we can modulate to change the entire immune microenvironment and essentially reverse the growth of tumours in mice, but we’ve only scratched the surface,” says Cooper. “This finding has the potential to open the door to safer, kinder therapies.”

Next steps towards kinder brain tumour treatments