Characterization of Intraepithelial Neutrophils in a Mouse Model of Ipmn

Document Type

Conference Proceeding

Publication Date

2-20-2026

Publication Title

Ann Surg Oncol

Keywords

myeloperoxidase, adult, animal experiment, animal model, conference abstract, controlled study, genotype, human, immune response, immunomodulation, immunosuppressive treatment, intraductal papillary mucinous tumor, mouse, mouse model, neutrophil, neutrophilia, nonhuman, pancreatic duct, pancreatic ductal carcinoma, precancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a well-known immunosuppressive microenvironment, however infiltrating neutrophils are observed in human pancreatobiliary intraductal papillary mucinous neoplasms (PB-IPMN) and their significance to disease initiation or progression is unclear. We previously described an inducible mouse model of duct-specific Kras activation and Pten loss that develops PB-IPMN and PDAC similar to human disease. Here we characterize whether this mouse model recapitulates the intraepithelial neutrophilia observed in patients. METHODS: Four mice with pancreatic ducts of the corresponding genotypes (KrasG12D;Pten-/-, KrasG12D;Pten+/-, KrasG12D;PtenWT, KrasWT;Pten-/-, KrasWT;PtenWT) were selected. One representative slide per mouse was stained for myeloperoxidase to detect neutrophils. Lesion and duct lumens were annotated, and computational analysis quantified neutrophil-lumen spatial relationships. Lumen geometry was used to quantify papillary architecture. RESULTS: Intraepithelial (<5 um from lumen) neutrophils were more abundant in IPMN than PDAC (29 vs 8.5 cells/region; KW p=3.3xl0"22); this persisted after total lesion area normalization (23 vs 11 cells/mm2; KW p=5.7∗10"9). A confirmatory analysis normalized to just the epithelial area showed a similar trend (IPMN vs PDAC: 480 vs 320 cells/mm2; KW p=0.095). Within IPMN, both local (100 urn lumen segment nearest the neutrophil) and global papillary complexity predicted intraepithelial neutrophil localization in logistic regression (local OR per SD = 1.17,95% CI 1.15-1.18, p < 0.005, global OR per SD = 1.04, 95% CI 1.03-1.05, p < 0.005). To test if intraepithelial localization preceded precancerous lesion formation, we analyzed non-lesion associated side and main ducts. Pten homozygous loss markedly increased intraepithelial neutrophil density (median 37.5 cells/mm2 vs 0 in wild type, p < 0.005), while Kras activation alone or in combination with Pten loss did not. CONCLUSIONS: In our mouse model, intraepithelial neutrophilia occurs across lesions and is greater in PB-IPMN compared to PDAC. In PB-IPMN, neutrophil localization is linked to papillary complexity. In normal ducts, Pten loss recruits neutrophils, while Kras activation blunts this response. These findings suggest an immune response exists during IPMN development. Defining the impact of these neutrophilepithelial interactions may inform use of immunomodulation in early disease.

Volume

33

Issue

1

First Page

S174

Last Page

S175

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