Project 458768

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has the lowest 5-year patient survival rate of all major cancer types. Immunotherapy is an increasingly promising approach to treating cancer patients. Immunotherapy is founded on our understanding of how cytotoxic lymphocytes (CTLs), a type of immune cell, can recognize and eradicate cancer cells. Immunotherapy enhances this process by, for instance, boosting CTLs to kill tumour cells with checkpoint inhibitors. However, this approach has shown limited success in PDAC, which can be attributed to the immunosuppressive factors inhibiting the CTLs from killing the tumour cells. A key factor may be the microbiome, which has increasing links to disease outcomes. In PDAC, microbiome compositional differences have been associated with patient survival. The aryl hydrocarbon receptor (AhR) is a key host cellular pathway responding to the microbiome. Activation of the AhR has been proposed to suppress CTL function. AhR agonists, such as indole compounds, can be produced by the microbiome. In fact, our lab has found that bacteria capable of producing indole compounds are enriched in PDAC patients with poor survival outcome. We hypothesize the microbiome limits CTL function in PDAC through production of AhR agonistic indole compounds and subsequently activation of the AhR pathway. Thus, in this project we will investigate the relationship between CTLs and the microbiome using murine tumour models and patient samples. In summary, this project proposes a novel therapeutic avenue of targeting AhR and the microbiome to reduce immunosuppression, enhance eradication of tumour cells by CTLs, and ultimately increase survival of PDAC patients.