Unveiling the Immunological Terrain of Pancreatic Ductal Adenocarcinoma: Strategies to Prompt Immunotherapy from Mendelian Randomization
Authors: Ni Peizan , Li Lilin , Du Kunpeng , Nov Pengkhun , Wang Duanyu , Wang Changqian , Kou Qianzi , Li Ying , Zhang Yangfeng , Zheng Chongyang , Fu Wen , Li Jiqiang 
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge in oncology, characterized by its immunosuppressive tumor microenvironment (TME) and resistance to immune checkpoint inhibitors (ICIs). This study leverages Mendelian randomization (MR) to elucidate the causal relationships between PDAC and a comprehensive array of immune cell traits, bacterial traits, inflammatory factors, and blood metabolites, aiming to uncover novel therapeutic targets and predictive biomarkers for PDAC. Utilizing datasets from large genome-wide association studies and employing the two-sample MR approach, we investigated the associations of 412 bacterial traits, 91 inflammatory factors, and 1400 blood metabolites with the risk of PDAC-related immune cell traits. 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. These findings illustrate the paradoxical nature of immune activation and suppression within the PDAC TME, underscoring the critical balance between immune surveillance and evasion mechanisms. Additionally, we unearthed significant associations between PDAC risk and specific bacterial traits, shedding light on the microbiome's potential role in shaping the immunological landscape of PDAC. Inflammatory factors and blood metabolites also emerged as crucial players, with our analysis revealing their complex interplay in influencing PDAC risk, reflecting the dual role of inflammation in tumorigenesis and the profound impact of metabolic reprogramming on immune competency. And 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, pointing to a systemic reshaping of the immune landscape in PDAC. Conversely, certain T-cell subsets showed increased associations, indicating potential targets for immunotherapeutic strategies. The bacterial trait associations, particularly with Collinsella and metabolic pathways like LACTOSECAT.PWY, highlight the gut microbiome's influence on immune modulation and PDAC pathogenesis. This study advances our understanding of PDAC's resistance to immunotherapies by delineating the genetic and immunological underpinnings of its complex TME. The integration of genetic profiling with advances in immunotherapy holds promise for tailoring treatments to individual tumor characteristics and overcoming PDAC's immunosuppressive barriers. Our findings underscore the potential of personalized immunotherapy and the modulation of metabolic pathways as promising strategies for PDAC treatment, opening new avenues for research and clinical translation in the era of precision oncology.