Immune Suppression in Pancreatic Cancer Linked to Gut Bacteria

Immune Suppression in Pancreatic Cancer Linked to Gut Bacteria
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University of Toronto and University Health Network (UHN) researchers published a report today in the journal Immunity that shows probiotic bacteria—often correlated with otherwise positive health effects—likely undermines immune response to pancreatic cancer. The scientists believe this knowledge could lead to more targeted treatments for a notoriously hard to treat cancer.

The findings indicated that lactobacillus, often regarded as beneficial to a health gut, can alter the function of immune cells called macrophages within the tumor environment and spur tumor growth.

“Most studies focus on positive correlations between the microbiome and cancer outcomes,” said Tracy McGaha, a professor of immunology at University of Toronto, a senior scientist at Princess Margaret Cancer Centre, UHN in a press release. “This work focused on negative correlations of the microbiome with cancer, and suggests that in some conditions, the constituency of the microbiome may have a negative impact.”

The researchers zeroed in on the role of the aryl hydrocarbon receptor (AHR). Previous research has shown that the protein regulates gene expression and enables beneficial inflammation and immune suppression in other parts of the body.

The team showed that Lactobacillus has an effect on macrophages by metabolizing tryptophan, an amino acid common in many foods. The indoles resulting from microbial tryptophan metabolization in turn activates AHR which, when deleted in inhibited in macrophages in AHR slowed pancreatic tumor growth.  It also led to better sensitivity to existing treatments and an increase in the number of inflammatory T cells, while activation of AHR negated these positive effects.

The researchers weren’t initially looking to the gut microbiome as a key driver of this activity, initially looking to simply better understand the role of AHR in tumor growth.

“We weren’t thinking about the microbiome at first, we were just interested in AHR as a factor in the tumor microenvironment,” McGaha said. “But when we blocked the mammalian genes that can activate AHR, it had no effect.”

This finding is what led the scientists to examine the role played by Lactobacillus bacteria, as its correlative role in AHR and reduced inflammation are known to enable cancer growth. The researchers first tested their hypothesis in mouse models of pancreatic cancer and then moved to human tissue samples and data from human trials to show that high expression of AHR correlates with disease progression, immune suppression and patient survival.

Pancreatic cancer is difficult to treat and has one of the lowest survival rates of solid tumor cancers. With the need for new and more effective treatments urgent, McGaha and UHN scientists have launched the PASS-01 clinical trial, in conjunction with other U.S.- and Canada-based cancer centers to find personalized predictors of patient response to chemotherapy.

Longer term, the investigators will continue to discover how immune cells interact with the microbiome with the intention to foster promising therapies such as fecal microbiota transplants, which have been hampered by the complexity and variety of gut bacteria. But McGaha, isn’t solely focused on the microbiome as the key.

“It could be possible to bypass the need to manipulate the microbiome, through precise targeting of the immune response to microbial metabolites,” said McGaha. “That’s a cool new direction we’d like to explore.”