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

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

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6 Scopus citations

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.

Original language	English (US)
Article number	3565
Journal	Cancers
Volume	13
Issue number	14
DOIs	https://doi.org/10.3390/cancers13143565
State	Published - Jul 2 2021

Bibliographical note

Funding 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 Information:
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.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Attenuated Salmonella typhimurium
Collagen
Collagenase
Desmoplasia
Pancreatic ductal adenocarcinoma
Targeted therapies
Therapeutic resistance
Tumor microenvironment

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers13143565

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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",

author = "Ebelt, {Nancy D.} and Vic Zamloot and Edith Zuniga and Passi, {Kevin B.} and Sobocinski, {Lukas J.} and Young, {Cari A.} and Blazar, {Bruce R.} and Manuel, {Edwin R.}",

note = "Funding 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 Information: 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. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Ebelt, Nancy D.

AU - Zamloot, Vic

AU - Zuniga, Edith

AU - Passi, Kevin B.

AU - Sobocinski, Lukas J.

AU - Young, Cari A.

AU - Blazar, Bruce R.

AU - Manuel, Edwin R.

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N2 - 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.

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Collagenase-expressing salmonella targets major collagens in pancreatic cancer leading to reductions in immunosuppressive subsets and tumor growth

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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