Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 25 June 2021 / Approved: 28 June 2021 / Online: 28 June 2021 (10:36:31 CEST)

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.

Journal reference: Cancers 2021, 13, 3565
DOI: 10.3390/cancers13143565

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.

Subject Areas

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

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