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Cancer cell Courtesy of the LRI EM Unit

Cancer cells have a frustrating habit of finding ways to shrug off the body’s immune system. They can make themselves invisible, slam on the immune system’s brakes or shield themselves in a protective environment.

And in some cases cancer cells can even rewire cellular signals to help them keep growing.

The TRAIL ‘death pathway’ is one example of this. TRAIL is an immune molecule that can specifically target and kill tumour cells. But bewilderingly, in some cancers it seems that TRAIL might actually promote their growth.

We want to understand which patients might benefit from such a therapy

Professor Henning Walczak

So what’s behind this troublesome double act? Our researchers at UCL sought to find out, and their latest study has offered some important insight into this phenomenon.

In a case of good cop turned bad, the researchers found that TRAIL can trigger cancer cells to release signalling molecules that encourage immune-dampening cells to flood around the tumour in mice, helping to boost its growth and shield it from attack.

But importantly, blocking TRAIL in the lab stopped this process and slowed down tumour growth in mice.

“Based on our data, we think that blocking TRAIL could work as a treatment for certain cancers in which the TRAIL system is faulty,” says lead researcher Professor Henning Walczak from UCL.

“Now we want to understand which patients might benefit from such a therapy.”

Switching allegiances

Launching an attack against cancer cells requires a collaborative effort from the immune system’s many components. While immune cells can’t talk to one another directly, they do have various methods of communication.

One involves the release of molecules called cytokines, or mini versions of these known as chemokines, which stimulate a response from other immune cells. TRAIL is a cytokine known for its anti-cancer effects in lab tests, causing tumour cells to die.

We realised that TRAIL wasn’t killing all cancer cells and that in some cases it was actually helping them

– Professor Henning Walczak

Some years ago, Walczak and others discovered that TRAIL could potentially be used as an approach to treat cancer because it not only kills cancer cells in the lab, but it leaves healthy cells unscathed. A number of treatments based on TRAIL have been developed since then, some of which are being tested in clinical trials.

But attempts at bringing these therapies into the clinic haven’t been plain sailing. It turns out that certain cancer cells have the ability to fend off these drugs, meaning the therapy had little benefit for some patients. This observation led Walczak to realise that TRAIL could also have a dark side.

“We realised that TRAIL wasn’t killing all cancer cells and that in some cases it was actually helping them,” recalls Walczak. “So we asked: could it be that the TRAIL pathway is hijacked by cancers and used to their advantage?”

And according to their latest results, that seems to be the case.

A change of scenery

To get to the bottom of this dual identity, the researchers bathed lung, pancreatic and bowel cancer cells in dishes laced with TRAIL and collected the molecules the cells subsequently spurted out.

They found that TRAIL triggered the release of a number of different cytokines and chemokines, some of which can support growing cancer cells and help recruit certain immune cells.

Next they found that these cellular messages were released by TRAIL through the action of another molecule called FADD, which normally helps to kill cancer cells by transmitting the TRAIL ‘death signal’.

To confirm these findings, the researchers removed FADD from lung cancer cells in mice. They expected lung tumours would grow rapidly. But instead the lack of FADD substantially diminished lung tumour growth.

When the team studied these tumours more closely, comparing them to mice that could still make FADD, they found much lower levels of the cancer-promoting cytokines and chemokines that TRAIL produces. On top of that, there were significantly fewer immune-dampening cells called ‘M2-like’ cells in the tissue around the tumours, known as the tumour microenvironment.

“We found that these TRAIL-stimulated cytokines and chemokines cause immune cells in the microenvironment to take on M2-like cell characteristics,” says Walczak. “These cells not only suppress the immune response against the tumour, but they also help the cancer grow and avoid immune recognition.”

They found that one of the cytokines, called CCL2, was the ringleader in boosting numbers of M2-like cells in the microenvironment. This isn’t the first study that’s picked out CCL2 as a culprit in this process either, suggesting that it could be a target for treatments. But it is the first to identify TRAIL, the factor that was so far thought to be the good cop by killing cancer cells, as the driving force behind CCL2 production.

But a key question remains: how does TRAIL act against cancer in some circumstances, while promoting it in others?

“Certain cancer-causing genetic mistakes can cause the TRAIL death pathway to become faulty,” Walczak explains. “This allows the tumour cells to use this system to their own advantage.”

One such genetic mistake affects a gene called KRAS. According to Walczak, this is found in almost all pancreatic cancer cells, and significant number of lung and bowel tumours too. So targeting the TRAIL pathway could potentially benefit a range of patients. And Walczak already has some ideas on how to go about this.

Going for gold

While this research highlights a crucial role for CCL2 in manipulating the tumour microenvironment, Walczak thinks that blocking TRAIL itself would be a better strategy.

“That would have the advantage of not only reducing CCL2 levels, but a whole host of other cytokines and chemokines that play a role in cancer development,” he says.

It’s going to be exciting taking this concept forward and see if it can help patients

– Professor Henning Walczak

“We could develop molecules that stick to TRAIL itself and stop its action, or design a molecule that stops it from producing all these harmful cytokines.”

It’s early days for this idea, but if such approaches are successful, next on the agenda would be to find out which patients could benefit. Already these results point towards those with faulty KRAS genes, but it could be that the TRAIL pathway is flawed in cancers caused by other genetic faults too.

“This is a major task,” says Walczak. “But it’s going to be exciting taking this concept forward and see if it can help patients.”

Justine

Hartwig, T. et al. (2017). The TRAIL-induced cancer secretome promotes a tumour-supportive immune microenvironment via CCR2. Molecular Cell. 65: 730-742. doi: 10.1016/j.molcel.2017.01.021.