Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is challenging to treat due to its immunosuppressive tumor microenvironment (TME) and resistance to immune checkpoint inhibitors. This study aims to discover new therapeutic targets and predictive biomarkers for PDAC. METHODS: Using Mendelian randomization, we studied causal relationships between PDAC and an array of immune cell traits, bacterial traits, inflammatory factors, and blood metabolites. We employed large genome-wide association study datasets and the two-sample MR approach for the investigation. RESULTS: Our results highlight suggestive evidence of associations between PDAC and distinct immune cell phenotypes, revealing nuanced alterations across monocytes, T-cells, B-cells, dendritic cells, and myeloid-derived suppressor cells. Our study provides a granular view of the PDAC-immune interface, identifying key immune cell traits and their associations with PDAC. For instance, our findings suggest a detrimental reduction in various monocyte traits, alongside a decrease in B-cell populations. Conversely, certain T-cell subsets showed increased associations, indicating potential targets for immunotherapeutic strategies. The bacterial trait associations, particularly with Collinsella and Ruminococcus torques, highlight the gut microbiome's influence on immune modulation and PDAC pathogenesis. Additionally, the traits concerning Interleukin-12 subunit beta levels and T-cell surface glycoprotein CD5 levels further indicate their function of this complex interaction. CONCLUSIONS: This study enhances our understanding of PDAC's resistance to immunotherapies and highlights the potential of personalized immunotherapy and metabolic pathway modulation in PDAC treatment. Our findings provide supportive evidence for research and clinical translation.