Two-step enhanced cancer immunotherapy with engineeredSalmonella typhimuriumsecreting heterologous flagellin.
We report a method of cancer immunotherapy using an attenuatedSalmonella typhimuriumstrain engineered to secreteVibrio vulnificusflagellin 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 engineeredSalmonellaappeared to induce the infiltration of abundant immune cells such as monocytes/macrophages and neutrophils via TLR4 signaling. Subsequent secretion of FlaB from colonizingSalmonellaresulted 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.
Laboratory of In Vivo Molecular Imaging, Institute for Molecular Imaging and Theranostics, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea.|Department of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju 61469, Republic of Korea.
Jin Hai
JH
Zheng
Laboratory of In Vivo Molecular Imaging, Institute for Molecular Imaging and Theranostics, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea.|Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Vu H
VH
Nguyen
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.|Department of Nuclear Medicine, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Hainan 570-208, China.
Sheng-Nan
SN
Jiang
Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea.
Seung-Hwan
SH
Park
Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Wenzhi
W
Tan
Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
Seol Hee
SH
Hong
Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Myung Geun
MG
Shin
Department of Hemato-Oncology, Chonnam National University Medical School, Jeonnam 58128, Republic of Korea.
Ik-Joo
IJ
Chung
Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Yeongjin
Y
Hong
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Hee-Seung
HS
Bom
Department of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju 61469, Republic of Korea.|Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Hyon E
HE
Choy
Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
Shee Eun
SE
Lee
Department of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju 61469, Republic of Korea. jjmin@jnu.ac.kr jhrhee@chonnam.ac.kr.|Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Joon Haeng
JH
Rhee
Laboratory of In Vivo Molecular Imaging, Institute for Molecular Imaging and Theranostics, Chonnam National University Hwasun Hospital, Jeonnam 58128, Republic of Korea. jjmin@jnu.ac.kr jhrhee@chonnam.ac.kr.|Department of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju 61469, Republic of Korea.|Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.|Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Jung-Joon
JJ
Min
D000818:Animals; D016764:Cell Polarity; D003110:Colonic Neoplasms / Q000473:pathology; D015169:Colony Count, Microbial; D005408:Flagellin / Q000378:metabolism*; D005818:Genetic Engineering; D045325:HCT116 Cells; D006801:Humans; D007167:Immunotherapy; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D012486:Salmonella typhimurium / Q000502:physiology*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D051198:Toll-Like Receptor 5; D005408:Flagellin; C416532:flaB flagellin