Comparative immune profiling of murine and human pancreatic cancer precursors reveals species- and lesion-dependent immune microenvironments

PURPOSE: This study aimed to comparatively characterize the immune microenvironment (iME) in murine and human precursor lesions of pancreatic ductal adenocarcinoma (PDAC) to better understand its role in pancreatic carcinogenesis. MATERIALS & METHODS: Tissue microarrays (TMAs) were constructed from 41 transgenic mice (140 samples including normal pancreas tissue, acinar-ductal metaplasia (ADM), pancreatic intraepithelial neoplasms (PanIN), and PDAC) and from 76 patients (221 samples including normal pancreas tissue, ADM, PanIN, intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and PDAC). OPAL™7 multiplex immunofluorescence was used for simultaneous detection of multiple immune cell markers (CD3, CD4, CD8, CD8a, FoxP3, PD-1, CD19, CD20, F4/80, CD68, CD163, Tryptase and Granzyme B), followed by software-assisted image-based quantification. RESULTS: The iME of all lesions was characterized by a predominance of CD3+ T lymphocytes over B lymphocytes, except for murine PanIN, which showed CD19+ B cell predominance. Both murine and human PDAC showed an immunosuppressive iME. However, precursor lesions differed markedly: murine ADM and PanIN showed no significant immune cell increases, while human ADM already displayed elevated mast cells, macrophages, T helper cells, and Tregs. Human ADM, PanIN and gastric-type IPMN showed a significant increase in CD8+ cytotoxic T cells compared to normal pancreas tissue, while cytotoxic T cells were decreased in PDAC. In contrast, human intestinal-type IPMN and MCN showed no increase in cytotoxic T cells. CONCLUSION: These findings highlight that the iME evolves during pancreatic carcinogenesis and differs significantly between species and lesion types. The immune landscape of murine models does not fully recapitulate that of human disease, emphasizing the need for caution when translating preclinical findings. Moreover, distinct immune profiles across human precursor subtypes suggest precursor-specific mechanisms of immune engagement.