Gut Bacteria May Determine Speed of Tumor Growth in Pancreatic Cancer
The population of bacteria in the pancreas increases more than a thousandfold in patients with pancreatic cancer and becomes dominated by species that prevent the immune system from attacking tumor cells. These are the findings of an early study conducted on pancreatic ductal adenocarcinoma, which is usually fatal within 2 years. Led by researchers at NYU School of Medicine, Perlmutter Cancer Center, and NYU College of Dentistry, the study was published by Pushalkar et al in Cancer Discovery.
Study Findings
Specifically, the study found that removing bacteria from the gut and pancreas by treating mice with antibiotics slowed cancer growth and reprogrammed immune cells to again “take notice” of cancer cells. Oral antibiotics also increased roughly threefold the efficacy of checkpoint inhibitors to bring about a strong antitumor shift in immunity.
Experiments found that in patients with pancreatic ductal adenocarcinoma, pathogenic gut bacteria migrate to the pancreas through the pancreatic duct. Once in the pancreas, this microbiome gives off cellular components that shut down the immune system to promote cancer growth, said the authors.
“While combinations of changes in genes like KRAS cause cells to grow abnormally and form pancreatic tumors, our study shows that bacteria change the immune environment around cancer cells to let them grow faster in some patients than in others, despite their having the same genetics,” said senior study coauthor George Miller, MD, Co-Leader of the Tumor Immunology Research Program at Perlmutter, and the H. Leon Pachter, MD, Professor in the Department of Surgery and Professor in Cell Biology at NYU Langone Health.
Underlying Mechanisms and Clinical Implications
“Our results have implications for understanding immune-suppression in pancreatic cancer and its reversal in the clinic,” said senior coauthor Deepak Saxena, PhD, Associate Professor of Basic Science and Craniofacial Biology at NYU College of Dentistry. “Studies already underway in our labs seek to confirm the bacterial species most able to shut down the immune reaction to cancer cells, setting the stage for new bacteria-based diagnostic tests, combinations of antibiotics and immunotherapies, and perhaps for probiotics that prevent cancer in high-risk patients.”
On the one hand, the research team theorizes that changes in the genes that cause abnormal cell growth in the pancreas might also change the immune response in ways that favor the growth of different bacterial species than are found in normal individuals. Alternatively, environmental factors like diet, other diseases, or common medications might cause bacterial changes in the gut that are reflected in the pancreatic microbiome.
Whatever the cause, the new study found that bacteria that are more abundant in pancreatic cancers—including groups of species called proteobacteria, actinobacteria, and fusobacteria—release cell membrane components (eg, lipopolysaccharides) and proteins (eg, flagellins) that shift macrophages into immune suppression. Experiments showed that eliminating bacteria using antibiotics restored the ability of immune cells to recognize cancer cells, slowed pancreatic tumor growth, and reduced the number of cancer cells present (tumor burden) by 50% in study mice.
The researchers found that “bad” bacteria in pancreas tumors trigger immune cell “checkpoints”—sensors on immune cells that turn them off when they receive the right signal. These checkpoints normally function to prevent the immune system from attacking the body’s own cells, but cancer cells hijack checkpoints to turn off immune responses that would otherwise destroy them. Checkpoint inhibitors are therapeutic antibodies that shut down checkpoint proteins to make tumors “visible” again to the immune system.
“Adding antibiotics improved the performance of a checkpoint inhibitor in a mouse model of [pancreatic ductal adenocarcinoma], as shown by an increase in T cells that could attack the tumors,” said first coauthor Mautin Hundeyin, MD, a postdoctoral fellow in Dr. Miller’s lab. “Our study confirmed that, similar to what has been observed in patients with pancreatic cancer, checkpoint inhibition alone did not protect mice. This may be because, in the immunosuppressive environment of the tumor, there are too few immune cells around to be activated.”
As a next step, the research team plans to soon begin recruiting patients into a clinical trial at Perlmutter Cancer Center to test whether a combination of antibiotics (ciprofloxacin and metronidazole) can improve the effectiveness of an anti–programmed cell death receptor 1 antibody in patients with pancreatic ductal adenocarcinoma.
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®.
