Our immune system protects us from many different threats, like bacteria, viruses, parasites and cancer.

It even protects us from some of our own immune cells.

Most of our immune cells attack the things that could make us sick. But without proper supervision, they can go too far and harm other healthy parts of the body.

The immune system has some built-in brakes called regulatory T cells (Tregs) to stop that happening. After other immune cells clear out a threat, Tregs come in and calm them down, allowing the body to start its healing process.

It takes a delicate balance of Tregs to keep a person healthy. Too few, and the immune system can become overactive and attack healthy cells, which can lead to autoimmune diseases. Too many, and they might make it easier for other threats, like cancer, to sneak through our defences and take hold.

That second problem is the focus of a new study at University College London (UCL). With Cancer Research UK funding, the researchers have uncovered a link between a “fog” of Tregs and an early, pre-cancerous form of the most common type of lung cancer, non-small cell lung cancer (NSCLC).

Now, with a fog-clearing drug, AI analysis tools and a new type of blood test, the team are using what they’ve learned to intercept lung cancer before it has the chance to start.

Spotting the precursors of cancer

We know that lung cancer doesn’t appear overnight. It comes after a cell mutates, or changes, and multiplies to form a group of pre-cancerous cells, or a lesion.

Lesions are an important sign that someone is at risk of cancer, but they can be hard to find, and not all of them go on to cause problems. Before we can do anything about them, scientists need better ways to spot them and identify which ones pose a threat.

Instead of looking for the lesions themselves, the UCL team, led by Dr James Reading and Professor Sam Janes, went searching for pre-cancer clues in the immune system.

“We were trying to see if the immune system could give us an early warning system to detect lung cancer before that cancer is fully fledged,” explains Reading.

“If we could measure that very early immune response in the blood, then that would give us an idea that somebody has an early and growing pre-cancer that we could intercept.”

They went looking for this response in two places: first, in the wider world, in people taking part in lung cancer screening programmes, and second, in the lab, in mouse models. By analysing blood and tissue samples from both, the team were able to look back in time and track how the immune system behaved before cancer appeared.

Across humans and mouse models, one key player emerged: Tregs.

“We’ve known that in invasive lung cancers these cells are a massive problem, but we never anticipated that they were coming on very intensely super early on during pre-invasive progression,” says Reading.

Across all their models, the team saw that a specific type of Tregs began to appear in the blood and tissues months or even years before lung cancer developed. As these cells built up, they seemed to be suppressing the immune system’s ability to find and clear lesions, making cancer more likely.

To test this idea, the researchers went back to the mouse models. If they’d interpreted what they were seeing correctly, clearing these Tregs would expose pre-cancerous lung cells to the body’s defences. They gave the mice a drug designed to do just that.

The results were dramatic. Mice that were treated with the fog-clearing drug were half as likely to develop lung cancer compared to those that had no treatment. And none of the mice that received the drug went on to develop large tumours.

The findings suggest that, in humans too, targeting Tregs could help intercept lung cancer before it takes hold, stopping some tumours from developing in the first place.

“This is the first time that we’ve been able to characterise that these cells that we know are a bad actor are really the key players in suppressing the immune system,” Reading says.

New outlook on lung cancer intervention

These findings are giving researchers a new way to think about tackling lung cancer.

“We’re hopefully moving from the current status quo of largely treating cancer when it develops towards tackling pre-cancerous disease,” says Janes. “This is called cancer interception, an exciting and emerging area of research which we hope will stop some pre-cancers from ever becoming cancers in the first place.”

The team now want to test their drug in a clinical trial. They’ve designed a prototype blood test that can detect the fog-causing Tregs, which they hope will help them find who’s most likely to benefit.

And, with the help of AI tools, the team are also optimising that test to make it as accurate as it can be.

“We’re using these tools to look across every single change in every measured cell across thousands of blood samples from people that did or did not go on to get cancer,” says Reading.

It’s a way to spot signs of lung cancer that might otherwise be overlooked.

“That type of pattern recognition across billions of data points is not something that the human brain has evolved to optimise for, not least at that scale,” Reading explains.

Although this work is still in its early phases, its potential is clear.

About 50,200 people are diagnosed with lung cancer in the UK each year, and 80 to 85% of them have NSCLC. If understanding Tregs helps spot more of these cases earlier, it would make a huge difference. More than 6 in 10 people diagnosed with stage 1 lung cancer survive the disease for at least five years, compared with less than 1 in 10 diagnosed at stage 4.

But clearing the fog could be a way to do even more. By focusing on cancer interception, Reading, Janes and their team are working to make sure fewer people ever have to be diagnosed with lung cancer at all.