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Title 

Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin

Authors 

J H ZhengV H NguyenS N JiangSeung Hwan ParkW TanS H HongM G ShinI J CHungY HongH S BomH E ChoyS E LeeJ H RheeJ J Min

Publisher 

American Association for the Advancement of Science

Issue Date 

2017

Citation 

Science Translational Medicine

Abstract 

We report a method of cancer immunotherapy using an attenuated Salmonella typhimurium strain engineered to secrete Vibrio vulnificus flagellin B (FlaB) in tumor tissues. Engineered FlaB-secreting bacteria effectively suppressed tumor growth andmetastasis inmousemodels and prolonged survival. By using Toll-like receptor 5 (TLR5)-negative colon cancer cell lines, we provided evidence that the FlaB-mediated tumor suppression upon bacterial colonization is associated with TLR5-mediated host reactions in the tumor microenvironment. These therapeutic effects were completely abrogated in TLR4 and MyD88 knockout mice, and partly in TLR5 knockout mice, indicating that TLR4 signaling is a requisite for tumor suppression mediated by FlaB-secreting bacteria, whereas TLR5 signaling augmented tumor-suppressive host reactions. Tumor microenvironment colonization by engineered Salmonella appeared to induce the infiltration of abundant immune cells such as monocytes/macrophages and neutrophils via TLR4 signaling. Subsequent secretion of FlaB from colonizing Salmonella resulted in phenotypic and functional activation of intratumoral macrophages with M1 phenotypes and a reciprocal reduction in M2-like suppressive activities. Together, these findings provide evidence that nonvirulent tumor-Targeting bacteria releasing multiple TLR ligands can be used as cancer immunotherapeutics.

ISSN 

1946-6234

Link 

http://dx.doi.org/10.1126/scitranslmed.aak9537

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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