Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer and Improves Immune Checkpoint Blockade

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

doi:10.20944/preprints202106.0638.v1

A peer-reviewed article of this Preprint also exists.

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. 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.

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 enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

Keywords

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

Subject

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer and Improves Immune Checkpoint Blockade

Abstract

Keywords

Subject

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