Exploiting the brain tumour environment to make better treatments

In a 6-part series, we’re exploring the major challenges that are holding back progress in the field of brain tumour research. This second instalment focuses on how understanding the environment in which a brain tumour grows could lead to better treatments.

Scientists are used to exploring unfamiliar territories. It’s thanks to centuries of these investigations that we understand most of the human body enough to fix things when they go wrong.

Unfortunately, some parts of the body remain somewhat of a mystery. And the brain is perhaps one of the greatest of these unexplored regions. This is one of the reasons why brain tumours are so difficult to treat.

As with other cancers, brain tumours are heavily influenced by their surroundings. So understanding how the cancer cells interact with their healthy counterparts and the structures around them should reveal long-anticipated ways to tackle them. But right now, we don’t know everything that goes on in this unique world.

This year we launched the Cancer Research UK Brain Tumour Awards to encourage experts from all types of research backgrounds to venture into this uncharted territory. We’ve teamed up with the Brain Tumour Charity to commit £18 million to tackle the six biggest challenges that are holding back progress in brain tumour research.

And it’s the aim of theme two in these awards to find out more about the brain tumour environment.

Much to explore

When Christopher Columbus landed in the Bahamas during his first voyage he could identify a ‘human’ because he’d seen many before. But understanding the complexities of the community, such as the language they spoke and how they interacted with each other, required a lot more work.

Professor Johanna Joyce, from the Ludwig Institute for Cancer Research at the University of Lausanne in Switzerland, says scientists are in a similar situation exploring the brain.

“Knowledge at the moment is still in its infancy,” she says. “While scientists have a grasp of the types of cells found in this unique environment, more information is needed on the interactions between the different immune cells and the tumour.”

The large, lower right structure is a mouse brain tumour. The brain tumour is embedded within a complex protein network. The proteins (red and green) interact with the tumour and are a very important part of the brain tumour microenvironment. Spencer Watson and Anoek Zomer, Joyce lab.

What’s in a brain tumour’s surroundings?

Dr Dirk Sieger, from the University of Edinburgh, is one of our scientists already looking into this extraordinary setting. He and his team have started to unpick what goes on between the brain tumour and immune cells when a tumour first starts to develop, revealing that the immune system in the brain isn’t as quiet as once thought.

“There are many different cell types within the brain tumour microenvironment; it’s a very complex mix of immune cells,” says Sieger.

Our immune system forms an intricate network of cells and signals that’s organised into two main cellular convoys. The first convoy (called the innate immune system) launches the initial response to danger, such as bacteria or viruses. While they keep the threat under control, the second convoy of cells (the adaptive immune system) has time to work out the exact nature of the attack and decide the best plan to neutralise the threat once and for all.

Scientists know that the diseased brain is home to cells from both convoys, but Sieger’s lab tests suggest they act differently compared to other places in the body.

“We know more about some immune cells in the brain than others,” says Sieger, who focuses on a type of immune cell called microglia, which are unique to the brain.

The first responders to brain tumours

Microglia are the first immune cells to interact with potentially cancerous brain cells, when they first undergo changes that could push them towards becoming tumour cells.

“In my studies we see microglia wrapping themselves around these changing cells and hugging them,” says Sieger. “We never usually see this reaction between this immune cell and healthy brain cells.”

Despite the microglia reacting to the changing cells, they don’t launch an attack.

“We’ve identified signals from more developed tumours that seem to attract these immune cells and influence them,” says Sieger. “The tumour manipulates them to help it grow.”

The details of this initial interaction are still unclear. The team now need to find out exactly how the brain tumour cells convince the microglia to keep quiet.

Tumours stop immune cell action

T cells are also in the immune cell community found in the brain. They’re in the second convoy of cells and are broadly divided into two teams.

The first team are called ‘helper’ T cells, which look out for warning signs that the body could be under attack. The second team are ‘killer’ T cells. Killer T cells chew up and destroy dangerous agents like viruses in response to signals from helper T cells.

“Both these functions in T cells are often inactivated in cancer,” says Joyce. “They often can’t recognise the cancer cells as foreign or dangerous.”

There are three possible reasons why T cells don’t usually respond to brain tumours.

First, the tumour cells don’t display ‘danger molecules’ on their surface, so helper T cells move past them and tumour cells go undetected.

Second, scientists think the first convoy of cells can sabotage the second. Immune cells that have initial contact with brain tumour cells can release molecules that stop T cells doing their job. Why this happens isn’t known.

Finally, the tumour itself can directly impact T cells.

“We know that the tumour can produce certain factors that turn helper T cells inactive,” says Dr Adel Samson, from the University of Leeds, who is looking at ways to turn T cells against brain tumours.

“So far immunotherapies in brain tumours have been a little disappointing.”

Samson says this is partly down to the way immunotherapy drugs work. Immunotherapy drugs, such as checkpoint inhibitors, have shown promise in treating other cancer types and work by releasing the brakes on the patient’s immune system so it can attack the cancer cells.

“But if the immune response doesn’t even exist then we’re not going to have any effect,” says Samson. “We know that there are very few killer T cells found in brain tumours, so one of the things new treatments need to do is encourage them to enter the tumour.”

“We can’t expect immune treatments that have worked in other tumour types to necessarily work in the same way in the brain,” explains Joyce. This is because the immune system in the brain behaves so differently compared to other areas of the body, and needs to be tackled with a different approach.

Samson is focusing his research on the brain. He’s enticing immune cells into the tumour microenvironment by using a common virus that replicates inside the tumour cells.

The immune system recognises the virus in the tumour cell and marks the cell as infected and, in theory, attacks.

Samson is already making progress. Results of his early-stage trial, that Cancer Research UK helped to fund, showed the virus is safe to give patients alongside their normal treatment.

“We found that in all nine patients the virus reached the brain tumour,” he says.

How might this benefit patients?

Even though a small number of clinical trials have started testing treatments that target the immune cells in the brain, there’s still a lot more to discover. Sieger says he sees treatments that exploit the cells in the tumour’s surroundings working alongside conventional therapy.

“We hope to not only make new therapies that could be given to existing patients to stop their tumours coming back after surgery, but also to find treatments that could be given alongside normal care when someone is first diagnosed,” he says.

“The best-case scenario is to develop a treatment that in some way could manipulate the patient’s own immune cells in the brain to actively detect tumour cells and turn against them.”

The next voyage

With so many different cells and interactions in the brain, there’s a lot to understand before new treatments will come. But Joyce says three stand out ways in which treatments could exploit the tumour’s environment are:

• Intercepting the conversation between different groups of immune cells.
• Blocking the chatter between tumours and immune cells that helps them grow.
• Making the tumour present itself to the immune system as dangerous.

Samson believes that an effective future treatment is likely to involve a combination of all three.

But before doctors and scientists can navigate us towards more successful brain tumour treatments, we need a map. We still don’t completely understand the inner workings of this specialised cell community, and so more work needs to be done that documents the conversations between these cells and the tumour. Only then can brain tumour immunotherapies move forward.

As Christopher Columbus found out, exploring any new realm takes time, but hopefully the cash injection and new ideas from diverse scientific fields will speed up the journey.

Gabi