Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Maleki Vareki, Saman

2nd Supervisor

Burton, Jeremy P

Co-Supervisor

Abstract

Providing adjuvants for immunotherapy for advanced and metastatic pancreatic adenocarcinoma (PDAC) is necessary for improved patient survival. Supplementation with Akkermansia muciniphila, a bacterium routinely found enriched in immunotherapy responders, has the potential to modulate the immune system and increase the efficacy of immunotherapy. We hypothesize that Akkermansia muciniphila has potential anti-tumour properties and can modulate the immune microenvironment of PDAC tumours. The treatment of PDAC cells with A. muciniphila bacterial cell-free supernatant, in vitro, resulted in decreased PDAC tumour cell count and migration, disruptions to the cell cycle, and increased immune activation. Additionally, in vivo, oral supplementation of A. muciniphila alone did not induce changes to the immune phenotype of tumours or the gut microbiota profile of PDAC tumour-bearing mice, but when combined with anti-PD-1 and anti-CTLA-4 immunotherapies altered the immune profile of tumours. This study demonstrates the anti-tumour and immunogenic effects of A. muciniphila supplementation alone and in combination with immunotherapy in a model of PDAC through mechanisms such as increased T-cell activation in vivo and decreased tumour cell proliferation and migration in vitro. Together, this work offers novel insights into the anti-tumour properties of A. muciniphila for adjunct therapy of PDAC in combination with immunotherapy and further elucidates the relationship between the gut microbiome and cancer therapeutics.

Summary for Lay Audience

Pancreatic cancer is one of the most deadly and difficult-to-treat cancers, with many patients not responding to treatment with conventional cancer therapeutics. Recent findings on other cancers, such as melanoma and colorectal cancer, provide evidence that the collection of bacteria within the gut called the gut microbiota, plays a major role in the effectiveness of cancer treatments. Previous studies have shown that people who respond well to immunotherapy, a cancer treatment that leverages the body’s immune system to fight against the tumour, often have increased levels of a beneficial bacterial species known as Akkermansia muciniphila in their gut. However, it is currently unknown whether administering these bacterial species to pancreatic cancer patients could enhance their response to immunotherapy. In this thesis, we studied how Akkermansia muciniphila could affect pancreatic cancer cells and the immune response against pancreatic tumours. Lab tests with the substances produced by Akkermansia muciniphila slowed the growth and the spread of pancreatic cancer cells. Additionally, we found that when Akkermansia muciniphila was given to mice orally in combination with immunotherapy, it affected the overall immune system and increased immune cell activation within the tumours. This research points to the potential of using Akkermansia muciniphila as a supplement to boost the effectiveness of immunotherapy in pancreatic cancer patients. It offers a new perspective on how gut bacteria can play a role in cancer treatment and opens up possibilities for future therapies that target the gut microbiome to improve cancer outcomes.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Wednesday, January 27, 2027

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