Abstract A061: Spatial Whole-Transcriptome Profiling Reveals Immune-Suppressive Stromal Niches and Associated Ductal Tumor Cell-State Programs in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked spatial heterogeneity and a highly variable immune microenvironment, ranging from myeloid-enriched, immune-suppressive regions to more immune-responsive niches. How tumor epithelial and stromal compartments contribute to these spatial immune states, and whether local microenvironments shift along a suppressive-to-responsive spectrum, remains incompletely understood. Here, we applied GeoMx spatial whole-transcriptome profiling to ductal and stromal regions of interest in human PDAC tissues to define compartment-specific transcriptional programs associated with distinct immune microenvironmental states. By comparing matched ductal and stromal compartments across higher and lower immunosuppressive stromal signatures, we identified coordinated changes in immune cell infiltration, inflammatory cytokine signaling, antigen presentation, myeloid cell activation, extracellular matrix remodeling, and epithelial stress-response programs. Immune-suppressive stromal regions were defined by macrophage, monocyte, interferon, and cytokine-related signatures. In parallel, matched ductal compartments displayed distinct epithelial cell-state programs associated with the surrounding myeloid- and cytokine-rich stromal context, suggesting that local stromal inflammation may link to tumor epithelial plasticity. To explore potential mechanisms linking stromal immune remodeling with epithelial plasticity, we examined candidate ligand-receptor interactions between ductal and stromal compartments. The oncostatin M (OSM)-OSMR axis emerged as one representative inflammatory communication pathway associated with myeloid-enriched suppressive niches. In particular, OSMR expression in ductal regions was linked to immune-derived inflammatory cues that may influence tumor epithelial states. This observation was further supported by complementary single-cell/spatial analyses, including OMNI, and monocyte/CAF–tumor cell co-culture models, which indicated that myeloid-associated signals can induce OSM/OSMR-associated inflammatory, stress-response, and epithelial plasticity programs in ductal tumor cells. Together, our studies demonstrate that spatial whole-transcriptome profiling of paired ductal and stromal compartments can identify localized immunosuppressive niches in PDAC and reveal associated tumor epithelial cell-state programs. By defining transcriptional features of myeloid-enriched stromal regions and identifying candidate inflammatory communication pathways, this work provides a spatial framework for understanding tumor-immune interactions in pancreatic cancer. More broadly, these findings suggest that immune states in PDAC are not fixed, but may reflect dynamic interactions among tumor epithelium, stromal inflammation, and myeloid cell-associated signaling.