The impact of Akkermansia muciniphila administration on immune system modulation and response to immunotherapy in pancreatic cancer.
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.