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FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer

BACKGROUND: Bladder cancer is a common disease worldwide with most patients presenting with the non-muscle-invasive form (NMIBC) at initial diagnosis. Postoperational intravesical instillation of BCG is carried out for patients with high-risk disease to reduce tumor recurrence and progression to mus...

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Autores principales: Zhang, Yang, Huo, Fan, Cao, Qiang, Jia, Ru, Huang, Qiju, Wang, Zhu A, Theodorescu, Dan, Lv, Qiang, Li, Pengchao, Yan, Chao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971803/
https://www.ncbi.nlm.nih.gov/pubmed/35361729
http://dx.doi.org/10.1136/jitc-2021-003939
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author Zhang, Yang
Huo, Fan
Cao, Qiang
Jia, Ru
Huang, Qiju
Wang, Zhu A
Theodorescu, Dan
Lv, Qiang
Li, Pengchao
Yan, Chao
author_facet Zhang, Yang
Huo, Fan
Cao, Qiang
Jia, Ru
Huang, Qiju
Wang, Zhu A
Theodorescu, Dan
Lv, Qiang
Li, Pengchao
Yan, Chao
author_sort Zhang, Yang
collection PubMed
description BACKGROUND: Bladder cancer is a common disease worldwide with most patients presenting with the non-muscle-invasive form (NMIBC) at initial diagnosis. Postoperational intravesical instillation of BCG is carried out for patients with high-risk disease to reduce tumor recurrence and progression to muscle invasive disease. However, BCG can also have side effects or be ineffective in some patients because it cannot enter the cancer cells. Thus, to improve the efficacy of BCG immunotherapy is the long-term pursuit of the bladder cancer field. METHODS: To increase the adhesion of BCG to the urothelium we overexpressed FimH, a mannose binding protein naturally used by uropathogenic Escherichia coli to adhere to human urothelium, onto the surface of BCG. The adhesion/internalization ability of rBCG-S.FimH was examined in mouse bladder by fluorescence microscopy. Preclinical evaluation of antitumor efficacy was carried out in orthotopic mouse models of bladder cancer and in human peripheral blood mononuclear cells. Mechanistic studies were carried out using toll-like receptor 4 (TLR4) knockout mice. Immune cells and cytokines in the serum, tumor and lymph nodes were analyzed by flow cytometry, PCR, ELISA and ELISPOT. RESULTS: rBCG-S.FimH exhibited markedly improved adhesion and more rapid internalization into urothelial cells than wild-type BCG, resulting in more potent antitumor activity in orthotopic murine models of bladder cancer. To our surprise, rBCG-S.FimH elicited a much more prominent Th1-biased immune response known to be positively correlated with BCG efficacy. Mechanistic studies using TLR4 knockout mouse showed that rBCG-S.FimH could induce enhanced dendritic cell activation and tumor antigen-specific immune response in a TLR4-dependent manner. Furthermore, human peripheral blood mononuclear cells stimulated by rBCG-S.FimH also showed better tumoricidal effects than those using wild-type BCG. CONCLUSION: rBCG-S.FimH is a novel BCG strain with significantly improved efficacy against bladder cancer. Since intravesical BCG immunotherapy is the first-line treatment for NMIBC, which accounts for more than 70% of all bladder cancer cases, our results provide a compelling rationale for clinical development.
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spelling pubmed-89718032022-04-20 FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer Zhang, Yang Huo, Fan Cao, Qiang Jia, Ru Huang, Qiju Wang, Zhu A Theodorescu, Dan Lv, Qiang Li, Pengchao Yan, Chao J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Bladder cancer is a common disease worldwide with most patients presenting with the non-muscle-invasive form (NMIBC) at initial diagnosis. Postoperational intravesical instillation of BCG is carried out for patients with high-risk disease to reduce tumor recurrence and progression to muscle invasive disease. However, BCG can also have side effects or be ineffective in some patients because it cannot enter the cancer cells. Thus, to improve the efficacy of BCG immunotherapy is the long-term pursuit of the bladder cancer field. METHODS: To increase the adhesion of BCG to the urothelium we overexpressed FimH, a mannose binding protein naturally used by uropathogenic Escherichia coli to adhere to human urothelium, onto the surface of BCG. The adhesion/internalization ability of rBCG-S.FimH was examined in mouse bladder by fluorescence microscopy. Preclinical evaluation of antitumor efficacy was carried out in orthotopic mouse models of bladder cancer and in human peripheral blood mononuclear cells. Mechanistic studies were carried out using toll-like receptor 4 (TLR4) knockout mice. Immune cells and cytokines in the serum, tumor and lymph nodes were analyzed by flow cytometry, PCR, ELISA and ELISPOT. RESULTS: rBCG-S.FimH exhibited markedly improved adhesion and more rapid internalization into urothelial cells than wild-type BCG, resulting in more potent antitumor activity in orthotopic murine models of bladder cancer. To our surprise, rBCG-S.FimH elicited a much more prominent Th1-biased immune response known to be positively correlated with BCG efficacy. Mechanistic studies using TLR4 knockout mouse showed that rBCG-S.FimH could induce enhanced dendritic cell activation and tumor antigen-specific immune response in a TLR4-dependent manner. Furthermore, human peripheral blood mononuclear cells stimulated by rBCG-S.FimH also showed better tumoricidal effects than those using wild-type BCG. CONCLUSION: rBCG-S.FimH is a novel BCG strain with significantly improved efficacy against bladder cancer. Since intravesical BCG immunotherapy is the first-line treatment for NMIBC, which accounts for more than 70% of all bladder cancer cases, our results provide a compelling rationale for clinical development. BMJ Publishing Group 2022-03-31 /pmc/articles/PMC8971803/ /pubmed/35361729 http://dx.doi.org/10.1136/jitc-2021-003939 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Clinical/Translational Cancer Immunotherapy
Zhang, Yang
Huo, Fan
Cao, Qiang
Jia, Ru
Huang, Qiju
Wang, Zhu A
Theodorescu, Dan
Lv, Qiang
Li, Pengchao
Yan, Chao
FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer
title FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer
title_full FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer
title_fullStr FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer
title_full_unstemmed FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer
title_short FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer
title_sort fimh confers mannose-targeting ability to bacillus calmette-guerin for improved immunotherapy in bladder cancer
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971803/
https://www.ncbi.nlm.nih.gov/pubmed/35361729
http://dx.doi.org/10.1136/jitc-2021-003939
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