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Pancreatic cancer cells - image courtesy of the London Research Institute EM Unit

Although cancer survival has doubled over the last 40 years, progress hasn’t been even: for some types of cancer, there has been little improvement in the outlook for patients.

This is particularly true of pancreatic cancer, where survival has barely improved for decades.

One ray of hope has been in immunotherapy – particularly in so-called ‘checkpoint inhibitor’ drugs which can trigger the immune system to attack a patient’s cancer.

But despite a growing list of cancers in which these drugs have shown promise – notably melanoma and lung cancer – pancreatic cancer hasn’t yet been included.

It seems that, in pancreatic tumours, there’s a fundamental problem – although checkpoint drugs do seem to be able to alert patients’ immune system to cancer’s presence, and switch it into ‘kill’ mode, pancreatic tumours are encapsulated in a densely packed, hard thicket of proteins and cells. And this environment seems to stop these cancer-targeting immune cells from infiltrating the tumour and destroying it. Trials to date have been disappointing.

But today a team of our scientists, led by Professor Owen Sansom and Dr Jennifer Morton, both based at our Beatson Institute in Glasgow, have published a study in Cancer Cell that might open up a way through these tumours’ defences.

When a friend turns bad

In recent years, Sansom’s research has focused on a molecule called CXCR2 – one of a family of different molecules which immune cells employ as a homing device to navigate to where they’re needed.

But Sansom’s team have also found that CXCR2 seems to play a role in cancer.

“From previous research, we’ve shown that CXCR2 somehow drives tumour growth in skin and bowel cancer in mice. So we decided to look and see whether the same thing was happening in pancreatic cancer.”

Researchers first analysed tumour tissue from people who’d had surgery for pancreatic cancer.

“We found high levels of CXCR2 on immune cells in the tumour surroundings,” Morton explains. “And the higher CXCR2 levels were, the worse the patients tended to have fared.”

So to unpick the role of CXCR2 in more detail, the team next turned to mice that had been genetically modified to develop pancreatic cancer; some mice had also been bred to carry a faulty CXCR2 gene, meaning their immune cells were missing their homing device.

“The mice lacking CXCR2 still developed pancreatic cancer and survived just as long as the others. But, remarkably, their tumours didn’t spread,” Sansom explained.

And when the team looked at these tumours under a microscope, they could see that particular types of immune cells called T cells – known to be involved in attacking tumour cells – had broken through the barrier and invaded the tumours.

It was interesting data, but a long way from a potential treatment – genetically modifying patients isn’t something that’s going to be possible in hospitals any time soon.

As well as this, as Morton explains, “patients are normally diagnosed at a late stage, when the disease has already started to spread. So treatment that stops cancers spreading wouldn’t be immediately useful.

“So we turned to experimental drugs that block CXCR2, and tested them in mice that had late stage pancreatic cancer.”

And this is where things started to look exciting.

Making immunotherapy work in pancreatic cancer

When the researchers treated these mice with an experimental CXCR2-targeting drug, they survived longer than the mice that weren’t given the drug.

“Not only that,” said Sansom, “it was even more effective when combined with the current gold standard of care for pancreatic cancer, a chemotherapy drug called gemcitabine. The tumours stopped spreading, and again we saw T cells had broken through the barrier and got inside the tumours.”

This last observation was particularly crucial. As we mentioned above, researchers suspect a key reason checkpoint drugs don’t work in pancreatic cancer is because the T cells they activate are blocked from entering tumours.

But given that CXCR2-blocking drugs somehow let the T cells in, this raised an interesting question: could they boost the effectiveness of checkpoint inhibitors?

T cell

A T-cell. Credit: NIAID/NIH (public domain), via Wikimedia Commons

Because the mice given the CXCR2 drug already had late stage pancreatic cancer, some didn’t survive long enough to have a second round of treatment with immunotherapy.

But tantalisingly, those that did and went on to be given a checkpoint inhibitor drug, often had a long lasting response.

Subverting the immune system

So what’s going on? What causes the high levels of CXCR2 in pancreatic tumours? Sansom’s team also looked in detail at the types of immune cells involved, to try to find out.

CXCR2 acts as a homing device for two particular forms of immune cells, both of which are known to form an important first line of defence against invaders – neutrophils and myeloid-derived suppressor cells.

When the body is damaged – for example via an open wound – damaged cells release ‘alarm’ molecules into the bloodstream. And neutrophils, via their CXCR2 receptors, use these molecules to guide them rapidly to the site of the problem, sirens blazing, to start containing and fixing the problem.

And while the role of myeloid-derived suppressor cells is less clear cut they seem to play a role, as their name suggests, in switching things off again when the damage is fixed – again using CXCR2 to guide them.

But in cancer, it seems these two types of cell are somehow attracted to the growing tumour, and are subverted to help it grow and spread. The high levels of CXCR2 are due to these tumours being filled with neutrophils and suppressor cells, at the expense of T cells. But working out the exact role of each type of cell in pancreatic cancer is no easy task.

“Neutrophils and suppressor cells seems to have different roles in early versus late stage disease,” says Sansom. “In early pancreatic tumours the neutrophils and myeloid-derived suppressor cells seem to slow tumour growth. But later on, they fuel the spread of the disease, which is ultimately what kills people.”

Sansom suspects there are three ways the neutrophils and myeloid-derived suppressor cells could be involved in pancreatic cancer:

  • They could be forming a vital part of the barrier around tumours, stopping tumour-destroying T cells from getting into the tumours
  • The toxic chemicals released by neutrophils – useful for combating infections – might drive further genetic damage in pancreatic tumours and provide signals for cancer cells to break away from the tumour
  • They change other tissues to make them more favourable for cancer cells to settle there (the ‘seed and soil’ theory of how cancer spreads)

Figuring out what they are doing at different stages of pancreatic cancer might be a turning point for switching them from foe back into a friend again.

The good news is that clinical trials for cancer are already on the horizon.

– Dr Jennifer Morton

Next steps…

While Sansom and others continue to unravel these complex issues, there’s a more pressing question. Could combining CXCR2 drugs with checkpoint inhibitors help make immunotherapy work for pancreatic cancer patients?

“The good news is that clinical trials for cancer are already on the horizon,” Morton tells us. “Various CXCR2-blocking drugs are already in late-phase clinical testing for inflammatory diseases like pancreatitis and lung disease, so doctors already know they are broadly safe and how best to give them to patients.”

Sansom agrees. “There is great appetite from pharmaceutical companies to figure out how to combine CXCR2-blockers with checkpoint inhibitors,” he says, “and early-phase clinical trials testing this are already underway for some types of cancer.”

It’s a desperately needed new approach for patients with a type of cancer that’s very hard to treat and gives some hope for a better future for people with pancreatic cancer.

And it could have wider implications for how checkpoint inhibitors are used too. Because even though, in the best result to date, more than half of patients with advanced skin cancer had a long lasting response to a duo of checkpoint drugs, that still leaves half whose cancers don’t respond, and the drugs haven’t shown anything like this kind of success against other types of cancer. So there’s an urgent need to find ways to boost their effectiveness.

Solving the mystery of how CXCR2 works is exciting science that could be another leap forward for immunotherapy.

 

Emma

Comments

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Emma September 2, 2016

Hi M. German,
Although exciting, the treatments we have talked about in the blog are still very experimental and not being tested in people with pancreatic cancer yet. The best person to ask about experimental treatments is your mother’s doctor. You can also call our nurses’ helpline (0808 800 4040, Monday – Friday 9-5) if you have any general questions about treatments.
Emma

M.German September 2, 2016

Hi I was just wondering if there is any more information or news about the development of this treatment.
My Mother was diagnosed with Pancreatic cancer 3 weeks ago. It is inoperable due to it’s close location to sensitive areas. We have also been told that she is too frail for chemotherapy. I have noticed however, that none of the doctors we have seen have mentioned immunotherapy. Any advice would be appreciated.

Barbara Cook July 7, 2016

Dear V Parry regarding early symptoms I was informed at the hospital when I asked the self same question that “possible signs” can include Pale putty coloured stools and “floaters” of same,Please bear in mind that these can happen anyway.I am so sorry for your loss and send you my best wishes.

V.Parry July 7, 2016

Is there any development in picking up/alerting medical staff and the individual to the development of this cancer? Having just lost a v.special sister 3wks from diagnoses to death, we would like to be aware of any early symptoms to this disease. Found the article informative, thank you.

Vibeke July 7, 2016

A very well written report that helps me to understand the complexity of the terrible pancreatic cancer that took my dad.

Fiona Connell June 3, 2016

wonderful work written about in a concise way which I could understand