Continuous tissue fields organize immune composition in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is commonly described by dividing tissue into distinct regions rich in specific cell types, such as myofibroblastic cancer-associated fibroblasts (myCAFs). However, it is uncertain if this organization persists as continuous spatial fields across the tumor. By examining spatial transcriptomic data from three Visium cohorts and an independent single-cell imaging dataset, researchers discovered that myCAFs create expansive fields extending over several millimeters.

As myCAF abundance increases, the immune landscape evolves smoothly from cytotoxic T cells and mast cells to SPP1 macrophages, monocytes, and neutrophils, without a discernible boundary separating the different immune states. In a separate group of 39 patients, all five immune populations shifted in the same direction, and three of them remained statistically significant compared to a spatial null model.

Additionally, a distinct field of epithelial abundance appeared to correlate with the same pattern of immune composition, suggesting that stromal architecture alone cannot explain immune organization. Single-cell spatial data unveiled another continuous organization within the tumor epithelium, where basal and classical cells form a unimodal spectrum.

Most tumor cells reside in intermediate states, while individual structures cover a significant portion of this spectrum. Basal identity peaks at the interfaces between tumor stroma and myCAFs, gradually decreasing with distance from these myCAF-rich regions. In summary, the study uncovers continuous spatial organization at two different scales in PDAC: variations in immune composition on a millimeter scale and single-cell contact-scale variation in tumor identity, both of which are not captured by classifying tissue into discrete neighborhoods.