Although immunotherapy – enlisting the immune system to attack tumors – is showing promise against some cancers, this is not the case in pancreatic cancer. Now, new research reveals there is a protein called CXCR2 that helps pancreatic cancer avoid and then exploit the immune system. Using mice, the researchers show drugs that block CXCR2 may offer a way to stop tumor spread and boost immunotherapy.
The study, led by researchers from the Beatson Institute in Glasgow, United Kingdom, is published in the journal Cancer Cell.
Over the last 40 years, the survival rate for many cancers has improved dramatically. However, for pancreatic cancer, a disease that is rarely detected in its early stages, survival remains pitifully low – the vast majority of patients do not live more than 5 years after diagnosis.
Hopes were raised when immunotherapy came on the scene. This approach – particularly in the form of “checkpoint inhibitors” that prime immune cells to attack tumors – is showing promise in several cancers, including melanoma and lung cancer. But results for pancreatic cancer have been disappointing.
An important factor in the failure of checkpoint drugs to attack pancreatic cancer has been the ability of tumors to surround themselves with a protective shield of proteins and cells that stop the primed immune cells from reaching and attacking the tumor.
Researchers at the Beatson Institute have been investigating a protein called CXCR2 for a while. They recently discovered CXCR2 plays a role in cancer – helping to drive tumor growth in mice with skin and bowel cancer. So they decided to investigate its role in pancreatic cancer.
First, the researchers analyzed tumor tissue from pancreatic cancer patients who had undergone surgery. They found high levels of CXCR2 on immune cells in the tumor surroundings. They also discovered that higher levels of CXCR2 correlated with worse outcomes for patients.
They then took a closer look at the role of CXCR2 by studying mice genetically engineered to develop pancreatic cancer. They also bred some of the mice to lack CXCR2.
Co-senior author Prof. Owen Sansom, of the Beatson Institute, explains what they found:
“The mice lacking CXCR2 still developed pancreatic cancer and survived just as long as the others. But, remarkably, their tumors didn’t spread.”
When they took a closer look, the team found in the mice lacking CXCR2 that immune system cells called T cells – known to be involved in attacking cancer cells – had broken through the protective shield and invaded the tumors.
In another set of experiments in mice with late stage pancreatic cancer, the researchers showed those treated with an experimental drug that blocks CXCR2 survived longer than untreated mice.
The team also found the CXCR2 inhibitor had a more powerful effect when combined with a chemotherapy drug called gemcitabine – the current gold standard of care for pancreatic cancer.
The combination stopped the tumors spreading, and on closer inspection, the team again saw that the T cells had broken through the protective shield and invaded the tumors.
Co-senior author Dr. Jennifer Morton, also of the Beatson Institute says that “one of the most striking effects of blocking CXCR2 was the rush of T cells into the tumor.”
This was a particularly crucial discovery – could it mean that a CXCR2 inhibitor might have the same boosting effect in immunotherapy and allow primed T cells access to the tumor?
The team went back to the mice with late-stage pancreatic cancer that had already been treated with CXCR2 inhibitor and treated remaining survivors with a checkpoint inhibitor drug. In most of these, the immunotherapy had a longer lasting effect.
Finally, the researchers tried to work out why CXCR2 appears to have such a key role in helping tumors spread. They concluded it has to do with two types of immune cell: neutrophils and myeloid-derived suppressor cells. CXCR2 acts as a type of homing device for these cells, helping them navigate to sites of injury or tissue damage.
When the immune system spots the injury or damage, it sends out alarm molecules into the bloodstream to summon neutrophils to start containing and fixing the problem. The neutrophils use their CXCR2 receptors to pick up the navigation direction from the alarm molecules.
Also, while less clear-cut, it appears the myeloid-derived suppressor cells also use CXCR2 to guide them to the site of the damage, except their role is to switch the process off again when the problem is fixed.
However, it seems that pancreatic cancer subverts the roles of these two types of cell and somehow exploits them to help tumors grow and spread. The researchers say this could be the reason the pancreatic tumors had such high levels of CXCR2 – because they were full of neutrophils and suppressor cells, at the expense of T cells.
There is still a lot of work to do to unravel exactly what is going on. Prof. Samson says it looks as if the roles of neutrophils and suppressor cells change as disease progresses, and explains:
“In early pancreatic tumors the neutrophils and myeloid-derived suppressor cells seem to slow tumor growth. But later on, they fuel the spread of the disease, which is ultimately what kills people.”
Even if further studies uncover the underlying mechanisms, there remains the practical clinical question of whether combining CXCR2 inhibitors with checkpoint inhibitors could make immunotherapy work for pancreatic cancer patients.
“The good news is that clinical trials for cancer are already on the horizon. 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.”
Dr. Jennifer Morton