Spatially Resolved Epithelial States Delineate Immunosuppressive Niches of Impaired Myeloid Antigen Presentation in PDAC

作者：Cameron Walker, Ruohan Wang, Hadeesha Piyadasa, Brooks Benard, Carl Pelz, Jenny Eng, Kevin Hawthorne, Rosalie C. Sears, Andrew J. Gentles, Tyler Risom, Michael Angelo · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.28.741300 · 研究领域：Single-cell and spatial transcriptomics、Pancreatic and Hepatic Oncology Research、Cancer Immunotherapy and Biomarkers

Abstract Bulk transcriptomic classifiers stratify pancreatic ductal adenocarcinoma (PDAC) into classical and basal-like subtypes with prognostic and therapeutic relevance, yet increasing evidence indicates that these epithelial programs frequently coexist within individual tumors. How these intermediate states affect the local tumor microenvironment remains poorly defined. Here, we integrate multiplexed ion beam imaging (MIBI) with bulk RNA sequencing to resolve epithelial subtype identity at the level of spatially contiguous cancer nests and quantify their associated microenvironments. Across 47 primary tumor samples from 34 patients, we identified classical, intermediate, and basal cancer cell states at single-cell resolution and delineated discrete cancer nests with mixed or dominant subtype compositions. Distance-resolved spatial analysis reveals that basal-rich cancer nests are surrounded by locally immunosuppressive microenvironments characterized by reduced expression of MHC class II and co-stimulatory molecules in proximal myeloid cells, independent of myeloid abundance. These regions are enriched in fibroblast-dominated neighborhoods and distinct cell-cell interaction architectures. Using EcoTyper analysis of two independent bulk RNA-seq cohorts, including an OHSU discovery cohort (N = 277 patients) and TCGA as a validation cohort (N = 147 patients), we identified poor-prognosis tumor ecotypes enriched for basal epithelial states that similarly exhibited depleted mye...