Tumor-Derived LAMB3 Drives Immunosuppressive LRRC15+ Fibroblast Formation During Pancreatic Ductal Adenocarcinoma Development

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive and desmoplastic tumor microenvironment (TME) that limits the efficacy of immunotherapy. However, the evolution of this immunosuppressive TME and the underlying mechanisms remain incompletely understood. Here, we construct a dynamic single-cell atlas spanning uninvolved adjacent pancreatic tissue (UNIN), intraductal papillary mucinous neoplasm (IPMN), and PDAC. We confirm the stepwise establishment of an immunosuppressive milieu, accompanied by the emergence of LRRC15⁺ fibroblasts as determinants. Functional assays further identify tumor-derived LAMB3 as a regulator of LRRC15⁺ fibroblast differentiation. Mechanistically, LAMB3 promotes FOSL2-dependent transcriptional activation of LRRC15 through the ITGB1/FAK/MAPK signaling axis, ultimately suppressing T cell cytotoxicity. Orthotopic models reveal that LAMB3 overexpression increases the LRRC15 positive area and impairs T cell cytotoxicity, whereas FAK inhibition partially reverses these effects. In parallel, LAMB3 knockdown reduces the LRRC15 positive area and improves the efficacy of PD-1 blockade. Moreover, glycolytic reprogramming in PDAC ductal cells upregulates LAMB3 expression and correlates with increased LRRC15⁺ fibroblast enrichment. Clinically, co-enrichment of LAMB3⁺ PDAC ductal cells and LRRC15⁺ fibroblasts is associated with inferior overall survival. Collectively, our findings define a dynamic ductal-fibroblast-immune multicellular axis underlying PDAC pathogenesis and provide insights into potential therapeutic strategies.

Keywords: cancer‐associated fibroblasts; cellular crosstalk; laminin; leucine‐rich repeat‐containing 15; pancreatic ductal adenocarcinomas.