Intratumoral Fibrin As A Novel Immunomodulatory Factor In Pancreatic Ductal Adenocarcinoma

In-situ coagulation is a common clinical feature of pancreatic ductal adenocarcinoma (PDAC) that presents a highly thrombotic and crosslinked insoluble fibrin (x-fibrin)-laden tumor stroma (FibTS). However, the specific impact of FibTS on immune cells behavior remains largely unexplored in this poorly infiltrated tumor. We aimed to elucidate how FibTS in PDAC regulates immune cell infiltration, polarization, and crosstalk that favors immunosuppressive microenvironment and tumor growth. We characterized human PDAC tissues by multiplex immunostaining and checked the spatial distribution of immune cells based on the presence of x-fibrin. We investigated how FibTS influences the infiltration of tumor-associated macrophage (TAM) and T-cell subtypes by utilizing two novel bioengineering models and mouse pancreatic tumor models. We identified two distinct variants of PDAC, fibrin-high (Fibhi) and fibrin-low (Fiblow). Our findings revealed that PDACs create their own FibTS by secreting the soluble fibrinogen into the tumor microenvironment (TME). FibTS in PDAC spatially regulated the infiltration of CD8+ T-cells and TAM subtypes. Creating physical barriers and biochemical niches, 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, leading to a deceleration in 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.