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Article

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

1
Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
2
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
3
Department of Pediatrics, Division of Blood and Bone Marrow Transplantation, University of Minnesota Medical School, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Sumit Sahni, Anubhav Mittal and Jaswinder Samra
Cancers 2021, 13(14), 3565; https://doi.org/10.3390/cancers13143565
Received: 25 June 2021 / Revised: 13 July 2021 / Accepted: 14 July 2021 / Published: 16 July 2021
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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.
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. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; targeted therapies; therapeutic resistance; tumor microenvironment; desmoplasia; collagen; collagenase; attenuated Salmonella typhimurium pancreatic ductal adenocarcinoma; targeted therapies; therapeutic resistance; tumor microenvironment; desmoplasia; collagen; collagenase; attenuated Salmonella typhimurium
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MDPI and ACS Style

Ebelt, N.D.; Zamloot, V.; Zuniga, E.; Passi, K.B.; Sobocinski, L.J.; Young, C.A.; Blazar, B.R.; Manuel, E.R. Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer Leading to Reductions in Immunosuppressive Subsets and Tumor Growth. Cancers 2021, 13, 3565. https://doi.org/10.3390/cancers13143565

AMA Style

Ebelt ND, Zamloot V, Zuniga E, Passi KB, Sobocinski LJ, Young CA, Blazar BR, Manuel ER. Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer Leading to Reductions in Immunosuppressive Subsets and Tumor Growth. Cancers. 2021; 13(14):3565. https://doi.org/10.3390/cancers13143565

Chicago/Turabian Style

Ebelt, Nancy D., Vic Zamloot, Edith Zuniga, Kevin B. Passi, Lukas J. Sobocinski, Cari A. Young, Bruce R. Blazar, and Edwin R. Manuel 2021. "Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer Leading to Reductions in Immunosuppressive Subsets and Tumor Growth" Cancers 13, no. 14: 3565. https://doi.org/10.3390/cancers13143565

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