In his newest published work in Cancer Cell, Raghu Kalluri, PhD, MD, at University of Texas MD Anderson Cancer Center, reports that fibrotic tissue supports immunity against cancer, contrary to previous hypotheses.
It has long been suspected that fibrotic tissue, which makes up 90% of pancreatic tumors and is composed mainly of collagen produced by myofibroblasts in the stroma of the pancreas, supports cancer growth and negatively impacts cancer therapies.
Now, according to Dr. Kalluri in a news release, “This supportive tissue that’s abundant in pancreatic cancer tumors is not a traitor as we thought but rather an ally that is fighting to the end. It’s a losing battle with cancer cells, but progression is much faster without their constant resistance. It’s like having a car with weak yet functioning brakes versus having one with no brakes.”
The change in thought was produced by a study that initially hypothesized myofibroblast-depleted mice treated with gemcitabine (the standard pancreatic cancer treatment) would show an improved response. “We did these experiments thinking that we would show the importance of myofibroblasts and fibrosis in pancreas cancer progression, but the results went completely against that hypothesis,” said Dr. Kalluri. What they actually saw in their myofibroblast-depleted mice was more invasive, aggressive pancreatic ductal adenocarcinomas.
“This paradigm-shifting study identifies the reason why the hedgehog-inhibitor trials failed,” said co-author Anirban Maitra, MD, from the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, in reference to a clinical trial combining the myofibroblast-depleting drug hedgehog inhibitor with gemcitabine to treat pancreatic cancer.
The trial was halted in 2012 due to faster disease progression in hedgehog-treated patients than in patients treated only with gemcitabine.
Fibrosis is not unique to pancreatic cancer. All tumors show some degree of fibrosis, but pancreatic cancer has the most. In humans, it was also shown that low-level fibrosis resulted in decreased survival.
The link between fibrosis and cancer immunity is the body’s natural hierarchy of defenses. “Cancer is one form of tissue injury. When our defense system detects damaged cells it sends soldiers to contain and repair the damage,” said Dr. Kalluri. “When it cannot remove the damaged cells and repair the injured area, our defensive fibrotic response tries to put a boundary around it, to contain it and prevent it from spreading.” Therefore, without fibrosis, the body’s back-up plan is nonexistent when immune cells fail in their fight.
In reference to another clinical trial, Dr. Maitra stated, “These findings are likely to account for rather modest results in a phase 1 clinical trial of immunotherapy alone for pancreatic cancer. But it’s just a negative study, because it suggests what might work for these patients.”
What might work is boosting immunity with therapy. Gene profiling in Dr. Kalluri’s study showed a suppression of genes associated with tumor immunity. Fewer disease-fighting T- and B-cells could infiltrate the fibrosis-poor tumors, but more regulatory T-cells were suppressing the immune response, possibly due to enhanced expression of immune checkpoint CTLA-4. With this knowledge, the researchers treated myofibroblast-depleted mice with ipilimumab, a drug developed by co-author Dr. Jim Allison to block CTLA-4, and saw a 60% increase in survival compared to untreated controls.
The team will continue working through these twists and turns by testing new hypotheses. They believe ipilimumab might be effective in patients with low levels of pancreatic fibrosis, while ipilimumab combined with a hedgehog inhibitor might be effective in patients with high levels of pancreatic fibrosis.
Previously in a collaborative study, Dr. Raghu found four sources of fibrosis-promoting cells in damaged tissue.
An estimated 46,420 Americans will be diagnosed with pancreatic cancer this year, some through blood tests developed at MD Anderson that look for specific biomarkers in pancreatic cancer, and 39,590 will die from the disease. Many deaths will be due to the strong resistance of pancreatic cancer to treatment.