Immunity: Gut bacteria linked to immune suppression in pancreatic cancer

Researchers at the University of Toronto and the University Health Network have shown how probiotics in the gut can disrupt immunity in pancreatic cancer, pointing the way to more personalized cancer treatments
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The researchers found that lactic acid bacteria -- a type of bacteria thought to promote gut health -- can alter the function of immune cells called macrophages in the environment of pancreatic tumors and stimulate cancer growth
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"Most research has focused on the positive relationship between the microbiome and cancer outcomes," said Tracy McGaha, a professor of immunology at T's Temerty School of Medicine and University Health.
Senior Scientist at the Network Princess Margaret Cancer Centre
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"This work focuses on the inverse association of the microbiome with cancer and shows that under certain conditions, the composition of the microbiome may have a negative impact

The journal Immunity published the findings today
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Macrophages are tissue-resident immune cells thought to play an important role in tumor growth and metastasis
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The researchers found that lactic acid bacteria affect macrophage function by metabolizing dietary tryptophan, an essential amino acid found in proteins in plant and animal foods

Indole, a class of metabolites produced by microbial tryptophan metabolism, activates the aryl hydrocarbon receptor, or AHR—a protein that regulates gene expression, resulting in beneficial inflammation and immunosuppression in other parts of the body
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The researchers found that loss or inhibition of AHR in macrophages reduced pancreatic cancer growth, improved sensitivity to treatment, and increased the number of inflammatory T cells
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Activation of the AHR hinders these beneficial effects

McGaha said he was surprised that the microbiome had such a large impact on AHR and immune function
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"We didn't start with the microbiome in mind, we were just interested in AHR as a factor in the tumor microenvironment," McGaha said

The researchers then turned to Lactobacillus, in part because previous studies have shown that the bacteria are associated with AHR activity and reduced inflammation, both of which promote cancer growth
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Working with Dana Philpott, a professor of immunology at T University's Germ-Free Animal Facility, they tested the bacteria's effects on mice that model pancreatic cancer surgery
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They also advanced the project with single-cell analysis techniques
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Single-cell analysis, a technique that provides genome-scale data in individual cells, was a huge draw, McGaha said when he moved to Toronto from the United States in 2015

"The technology was fairly new at the time, but it was invaluable for us seeing the population responses in the gene expression patterns of macrophages and other immune cells, and what's going on around them
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The researchers later used tissue samples and data from human trials to show that high AHR expression was associated with disease progression, immunosuppression, and patient survival
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Pancreatic cancer is notoriously difficult to treat
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Despite being relatively rare, it ranks third among the deadliest cancers in Canada, and survival for people with the disease has not improved as much as other cancers over the past 30 years

To help address the urgent need for more effective treatments, McGaha is working with UHN clinical scientists on a clinical trial called PASS-01
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The study, in collaboration with other cancer centers in Canada and the United States, aimed to discover individualized predictors of patients' response to chemotherapy

The team will collect stool samples before and after chemotherapy to look for lactobacillus enrichment, and whether the bacteria are associated with treatment response, patient survival, and what they observe about its role in the tumor environment
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"It's exciting to be involved in translational research as a basic scientist, and it's nice to see internal medicine scientists take an interest in this work," McGaha said
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In the long term, McGaha said, his lab will gain a deeper understanding of how immune cells interact with the microbiome
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The researchers hope to improve promising treatments, such as fecal microbiota transplantation, hampered by the complexity and diversity of gut bacteria, or try a new approach
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"By pinpointing the immune response to microbial metabolites, we have the potential to not need to manipulate the microbiome," McGaha said
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"This is a cool new direction we want to explore
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article title

Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity