Stromal fibrin shapes immune infiltration landscape of pancreatic ductal adenocarcinoma.

Abstract

In pancreatic ductal adenocarcinoma (PDAC), in-situ coagulation creates a thrombotic, crosslinked fibrin (x-fibrin)-rich tumor stroma (FibTS), whose impact on immune cell behavior remains unclear. We aimed to elucidate how FibTS in PDAC regulates immune cell infiltration, polarization, and crosstalk that favors immunosuppressive microenvironment and tumor growth. We assessed the spatial distribution of immune cells by multiplex immunostaining of human PDAC tissues, along with novel bioengineering and mouse tumor models. We investigated how FibTS influences the infiltration of tumor-associated macrophage (TAM) and T-cell subtypes and identified two distinct variants of PDAC, fibrin-high (Fib^hi) and fibrin-low (Fib^low). Our findings reveal that PDAC cells secrete fibrinogen and thrombin to form FibTS, which acts as a physical barrier and biochemical niche that restricts CD8⁺ T-cell and TAM penetration into the tumor. The FibTS impeded immune cell penetration from the tumor stroma into the tumor parenchyma. Selective inhibition of FibTS formation by genetic and pharmacological tools altered the infiltration patterns of CD8⁺ T-cells and TAMs, decelerating PDAC growth. This study demonstrates that the barrier function of FibTS is crucial for immune evasion, particularly against macrophage and T-cell activity, presenting a potential therapeutic strategy to reshape the immune landscape within PDAC and slow tumor progression.