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

Nancy D Ebelt; Vic Zamloot; Edith Zuniga; Kevin B Passi; Lukas J Sobocinski; Cari A Young; Bruce R Blazar; Edwin R Manuel

doi:10.3390/cancers13143565

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

Cancers (Basel). 2021 Jul 16;13(14):3565. doi: 10.3390/cancers13143565.

Authors

Nancy D Ebelt¹, Vic Zamloot¹, Edith Zuniga¹, Kevin B Passi¹, Lukas J Sobocinski¹, Cari A Young², Bruce R Blazar³, Edwin R Manuel¹

Affiliations

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.

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.

Keywords: attenuated Salmonella typhimurium; collagen; collagenase; desmoplasia; pancreatic ductal adenocarcinoma; targeted therapies; therapeutic resistance; tumor microenvironment.

Abstract

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