Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPMN) is crucial. However, early intervention must be balanced against overtreatment of low-risk lesions that are unlikely to progress, underscoring the need to better understand molecular alterations in neoplastic cells and changes in the tumor microenvironment (TME) that drive the progression of IPMNs. In this study, we characterized alterations in the TME of IPMNs as they progressed to high-grade dysplasia, using immunohistochemistry to quantify immune cell density and activation status in more than 100 well-characterized human IPMN samples. Analyses revealed progression to a more immunosuppressive TME in high-grade IPMN compared with low-grade IPMN, characterized by elevated expression of immune checkpoint molecules (PD-L1, TIM3, VISTA), increased density of macrophages, and decreased density of cytotoxic T cells. Intriguingly, the alterations in macrophages were limited to focal regions of high-grade dysplasia, while T-cell alterations affected the entire IPMN. Additionally, elevated VISTA expression was associated with poorer clinical outcome after IPMN resection in an independent cohort. These findings provide important insights into the interplay between the immune microenvironment and IPMN progression, highlighting potential targets to modify the TME for cancer interception. © 2025 The Pathological Society of Great Britain and Ireland.