Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer Leading to Reductions in Immunosuppressive Subsets and Tumor Growth

Abstract

Simple Summary The deposition of fibrotic tissue within pancreatic tumors acts as a physical barrier to therapeutic treatment. Collagen constitutes a large part of this barrier and serves as an ideal target to improve delivery and efficacy of anti-cancer treatments. This study characterizes a novel bacterial-based agent engineered to degrade collagens present only in pancreatic tumor tissue. Treatment using our collagen-degrading bacteria in mouse models of pancreatic cancer resulted in significant decreases in intratumoral collagen content and pro-tumor immune cell subsets, ultimately enhancing the efficacy of immunotherapy. These results support the idea that overcoming fibrosis in pancreatic cancer can dramatically improve therapeutic outcomes. Abstract Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to decreases in immunosuppressive subsets, tumor proliferation and viability. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment that may be more conducive to immunotherapy.