NK cell co-localization with epithelial cells in pancreatic cancer is influenced by fibroblasts and ECM components

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and common type of pancreatic cancer. PDAC has a dense, fibrotic tumor microenvironment (TME) that restricts immune cell infiltration and contributes to poor immunotherapy responses. While T cell-based therapies have been largely ineffective, natural killer (NK) cells-which kill tumor cells without requiring MHC recognition-offer a promising alternative. However, their role in the PDAC TME remains poorly understood. Here, we show that NK cells are present, active, and spatially associated with malignant epithelial cells in human PDAC. Using cytometry by time-of-flight (CyTOF) in murine PDAC, imaging mass cytometry (IMC) in human tumors, and CellChat analysis of a human PDAC scRNAseq dataset, we found that NK cells interact with extracellular matrix (ECM) components via CD44. Fibroblast-rich, desmoplastic regions appear to limit NK cell infiltration. In vitro 2D and 3D assays revealed that CD44 neutralization significantly enhances NK cell matrix invasion. These findings highlight the underappreciated presence and tumor cell-proximal localization of NK cells in PDAC and identify ECM-CD44 interactions as a barrier to their infiltration. Targeting these interactions may enhance NK cell-based immunotherapy in PDAC.