3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure

作者：Ashley Kiemen, Cristina Almagro-Pérez, Valentina Matos, André Forjaz, Alicia M. Braxton, Lucie Dequiedt, Jeeun Parksong, Courtney D. Cannon, Xuan Yuan, Sarah M. Shin, Jaanvi Mahesh Babu, Elizabeth D. Thompson, Toby C. Cornish, Won Jin Ho, Laura D. Wood, Pei‐Hsun Wu, Arrate Muñoz‐Barrutia, Ralph H. Hruban, Denis Wirtz · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.08.03.606493 · 被引用次数：8 · 研究领域：Pancreatic and Hepatic Oncology Research、Pancreatitis Pathology and Treatment、Cancer Immunotherapy and Biomarkers

SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, in part due to its unique stromal and immune microenvironment. Pancreatic intraepithelial neoplasia, or PanIN, is the main precursor lesion to PDAC. Recently it was discovered that PanINs are remarkably abundant in the grossly normal pancreas, suggesting that the vast majority will never progress to cancer. Here, through construction of 48 samples of cm 3 -sized human pancreas tissue, we profiled the immune microenvironment of 1,476 PanINs in 3D and at single-cell resolution to better understand the early evolution of the pancreatic tumor microenvironment and to determine how inflammation may play a role in cancer progression. We found that bulk pancreatic inflammation strongly correlates to PanIN cell fraction. We found that the immune response around PanINs is highly heterogeneous, with distinct immune hotspots and cold spots that appear and disappear in a span of tens of microns. Immune hotspots generally mark locations of higher grade of dysplasia or locations near acinar atrophy. The immune composition at these hotspots is dominated by naïve, cytotoxic, and regulatory T cells, cancer associated fibroblasts, and tumor associated macrophages, with little similarity to the immune composition around less-inflamed PanINs. By mapping FOXP3+ cells in 3D, we found that regulatory T cells are present ...