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

Cited 166 time in scopus
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Title
Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin
Author(s)
J H Zheng; V H Nguyen; S N Jiang; Seung Hwan Park; W Tan; S H Hong; M G Shin; I J CHung; Y Hong; H S Bom; H E Choy; S E Lee; J H Rhee; J J Min
Bibliographic Citation
Science Translational Medicine, vol. 9, no. 376, pp. eaak9537-eaak9537
Publication Year
2017
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
Publisher
Amer Assoc Advancement Science
DOI
http://dx.doi.org/10.1126/scitranslmed.aak9537
Type
Article
Appears in Collections:
Jeonbuk Branch Institute > Biological Resource Center > 1. Journal Articles
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