Supportive Tumor Tissue Surrounding Cancer Cells Hinders Pancreatic Cancer Progression, Preclinical Study Reports
Fibrous tissue long suspected of making pancreatic cancer worse actually supports an immune attack that slows tumor progression but cannot overcome it, scientists at The University of Texas MD Anderson Cancer Center reported in the journal Cancer Cell.
“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,” said study senior author Raghu Kalluri, PhD, MD, Chair of Cancer Biology. “It’s like having a car with weak yet functioning brakes vs having one with no brakes.”
The team’s findings point to a potential new avenue for guiding treatment, including immunotherapy, and offer an explanation for the failure of a promising combination drug approach in clinical trials.
“Cancer is one form of tissue injury. When our defense system detects damaged cells, it sends soldiers to contain and repair the damage,” Dr. Kalluri said. “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.”
Study Results Consistent With Failed Clinical Trial
The investigators used genetically engineered mouse models that allowed depletion of myofibroblasts in pancreatic cancer. Myofibroblasts compose a major portion of supportive tissue called stroma and also produce collagen, which serves as a scaffold for wound-healing and tissue regeneration. Up to 90% of a pancreas tumor can consist of fibrotic support tissue.
When the scientists depleted myofibroblast production in mice with either early- or later-stage pancreatic ductal adenocarcinoma, their tumors became much more invasive, aggressive, and lethal.
“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,” Dr. Kalluri said.
Since myofibroblasts and collagen are thought to block chemotherapy, the team treated their myofibroblast-depleted mice with gemcitabine, the standard treatment for pancreatic cancer. The drug did not have any effect on the disease course or improve survival.
These results track those of a major clinical trial that combined a myofibroblast-depleting drug called a hedgehog inhibitor with gemcitabine to treat pancreatic cancer patients. The trial was stopped in 2012 when an interim analysis showed the patients taking the combination had faster disease progression than the control group that took only gemcitabine, a surprising result.
Low Levels of Myofibroblasts Lead to Poor Survival
“This paradigm-shifting study identifies the reason why the hedgehog-inhibitor trials failed,” said coauthor Anirban Maitra, MD, Professor of Pathology and Scientific Director of the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research at MD Anderson.
All solid tumors include some degree of fibrosis, Dr. Maitra said, but not as much as pancreatic cancer.
The team's analysis of pancreatic tumors from 53 patients showed low levels of tumor myofibroblasts are associated with decreased survival.
Study findings are consistent with pathologic evidence that tumors with more fibrotic tissue more closely resemble normal pancreas tissue, indicating a better prognosis for patients, even though lab experiments indicated those tumors should be more aggressive, Dr. Maitra said.
“These findings also are likely to account for rather modest results in a phase I clinical trial of immunotherapy alone for pancreas cancer,” Dr. Maitra said. “But it’s not just a negative study, because it suggests what might work for these patients.”
And what might work hinges on immune checkpoint blockade.
Immune System Connection
To understand the cause of the swift progression, the team conducted gene-expression profiling and RNA sequence analysis comparing control tumors to myofibroblast-depleted tumors.
Genes associated with tumor immunity were suppressed and fewer T cells and B cells infiltrated the myofibroblast-depleted tumors. The proportion of regulatory T cells, which suppress immune response, increased. They found greater expression of the immune checkpoint CTLA-4, which shuts down immune response.
The researchers then set up a new experiment using ipilimumab (Yervoy), freeing T cells to attack tumors. Mice with depleted myofibroblasts who were treated with ipilimumab to stifle CTLA-4 had an average survival increase of 60% compared to untreated control mice and those with either depleted myofibroblasts or treated with ipilimumab alone.
These findings suggest that ipilimumab might work for patients with low levels of fibrosis in their tumors, Dr. Kalluri noted. Combining ipilimumab with a hedgehog inhibitor is likely to work better for those with high fibrosis levels. The Kalluri laboratory is exploring these issues.
Dr. Kalluri is the corresponding author for the Cancer Cell article.
This research was funded by grants from the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, MD Anderson’s Metastasis Research Center, the OncoSuisse MD/PhD Scholarship, the Swiss National Science Foundation Fellowship, and a research fellowship from Deutsche Forschungsgemeinschaft.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
