Zheng, Jin Hai; Nguyen, Vu H; Jiang, Sheng-Nan; Park, Seung-Hwan; Tan, Wenzhi; Hong, Seol Hee; Shin, Myung Geun; Chung, Ik-Joo; Hong, Yeongjin; Bom, Hee-Seung; Choy, Hyon E; Lee, Shee Eun; Rhee, Joon Haeng; Min, Jung-Joon
Science translational medicine
2017Feb ; 9 ( 376 ) :.
PMID : 28179508
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Zheng, Jin Hai -
Nguyen, Vu H -
Jiang, Sheng-Nan -
Park, Seung-Hwan -
Tan, Wenzhi -
Hong, Seol Hee -
Shin, Myung Geun -
Chung, Ik-Joo -
Hong, Yeongjin -
Bom, Hee-Seung -
Choy, Hyon E -
Lee, Shee Eun -
Rhee, Joon Haeng -
Min, Jung-Joon -
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 and metastasis in mouse models 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. CI - Copyright ??2017, American Association for the Advancement of Science.
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