Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the deadliest common cancer. While immunotherapy has improved outcomes in other solid tumors, results for PDAC remain poor. The pancreas produces digestive proteases, which are often elevated in diseased states. These proteases (e.g., trypsin, chymotrypsin, elastase) can activate secondary proteases (e.g., metalloproteinases (MMPs), cathepsins) that contribute to pathophysiology through increased cell surface receptor cleavage. We hypothesize that increased protease activity in PDAC facilitates immune evasion through immune receptor cleavage.Methods: The Rapid Assay for Protease Detection (RAPD) is a novel assay developed at UCSD, using fluorescent charge-changing peptide substrates to detect protease activity. We analyzed protease activity levels in plasma samples from PDAC patients (N=23) and healthy subjects (N=10). We also investigated the effects of specific proteases and patient plasma on major histocompatibility complex (MHC)-1 and MHC-2, two cell surface receptors that are essential for antigen presentation. Receptor loss in human PDAC cells (PANC-1) in vitro was quantified using flow cytometry and immunofluorescent imaging. Results: We observed elevated cathepsin-S, chymotrypsin, and MMP-2 levels in PDAC plasma compared to healthy control plasma. Early data suggest trypsin and cathepsin-S increase MHC-1 and MHC-2 cleavage in vitro. Incubation of cells with PDAC patient plasma possessing higher protease activity reduced MHC-1 and MHC-2 expression on cells to a greater extent than normal plasma. Conclusions: These findings suggest that digestive proteases may contribute to immune evasion in PDAC by promoting immune receptor cleavage. Ongoing studies are exploring other immune receptors and the potential of protease inhibitors to prevent receptor cleavage. Future experiments will test combinations of protease inhibitors with immunotherapy in vivo.