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.
Bibliographical noteFunding Information:
Conflicts of Interest: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; Research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre biopharmaceuticals, Carisma Therapeutics, Inc., and is a co-founder of Tmunity Therapeutics. All other authors declare no conflicts of interest.
Funding: This research was partially funded by a COH Shared Resources grant (ERM). Research reported in this publication included work performed in the Molecular Pathology, Animal Resource Center, Small Animal Imaging and Light Microscopy Digital Imaging cores supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Attenuated Salmonella typhimurium
- Pancreatic ductal adenocarcinoma
- Targeted therapies
- Therapeutic resistance
- Tumor microenvironment