In vitro Evidence of Human Immune Responsiveness Shows the Improved Potential of a Recombinant BCG Strain for Bladder Cancer Treatment

Rodriguez, D; Goulart, C; Pagliarone, AC; Silva, EP; Cunegundes, PS; Nascimento, IP; Borra, RC; Dias, WO; Tagliabue, A; Boraschi, D; Leite, LCC

In vitro Evidence of Human Immune Responsiveness Shows the Improved Potential of a Recombinant BCG Strain for Bladder Cancer Treatment

Rodriguez, D Goulart, C

Pagliarone, AC Silva, EP Cunegundes, PS Nascimento, IP Borra, RC Dias, WO Tagliabue, A Boraschi, D Leite, LCC

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Publication Type:: Journal Article
Citation:: Frontiers in Immunology, 2019, 10 (JUN)
Issue Date:: 2019-01-01

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Field	Value	Language
dc.contributor.author	Rodriguez, D	en_US
dc.contributor.author	Goulart, C https://orcid.org/0000-0003-2981-1934	en_US
dc.contributor.author	Pagliarone, AC	en_US
dc.contributor.author	Silva, EP	en_US
dc.contributor.author	Cunegundes, PS	en_US
dc.contributor.author	Nascimento, IP	en_US
dc.contributor.author	Borra, RC	en_US
dc.contributor.author	Dias, WO	en_US
dc.contributor.author	Tagliabue, A	en_US
dc.contributor.author	Boraschi, D	en_US
dc.contributor.author	Leite, LCC	en_US
dc.date.available	2019-06-10	en_US
dc.date.issued	2019-01-01	en_US
dc.identifier.citation	Frontiers in Immunology, 2019, 10 (JUN)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/134329
dc.description.abstract	Copyright © 2019 Rodriguez, Goulart, Pagliarone, Silva, Cunegundes, Nascimento, Borra, Dias, Tagliabue, Boraschi and Leite. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The live attenuated mycobacterial strain BCG, in use as vaccine against tuberculosis, is considered the gold standard for primary therapy of carcinoma in situ of the bladder. Despite its limitations, to date it has not been surpassed by any other treatment. Our group has developed a recombinant BCG strain expressing the detoxified S1 pertussis toxin (rBCG-S1PT) that proved more effective than wild type BCG (WT-BCG) in increasing survival time in an experimental mouse model of bladder cancer, due to the well-known adjuvant properties of pertussis toxin. Here, we investigated the capacity of rBCG-S1PT to stimulate human immune responses, in comparison to WT-BCG, using an in vitro stimulation assay based on human whole blood cells that allows for a comprehensive evaluation of leukocyte activation. Blood leukocytes stimulated with rBCG-S1PT produced increased levels of IL-6, IL-8, and IL-10 as compared to WT-BCG, but comparable levels of IL-1β, IL-2, IFN-γ, and TNF-α. Stimulation of blood cells with the recombinant BCG strain also enhanced the expression of CD25 and CD69 on human CD4+ T cells. PBMC stimulated with rBCG-S1PT induced higher cytotoxicity to MB49 bladder cancer cells than WT-BCG-stimulated PBMC. These results suggest that the rBCG-S1PT strain is able to activate an immune response in human leukocytes that is higher than that induced by WT-BCG for parameters linked to better prognosis in bladder cancer (regulation of immune and early inflammatory responses), while fully comparable to WT-BCG for classical inflammatory parameters. This establishes rBCG-S1PT as a new highly effective candidate as immunotherapeutic agent against bladder cancer.	en_US
dc.relation.ispartof	Frontiers in Immunology	en_US
dc.relation.isbasedon	10.3389/fimmu.2019.01460	en_US
dc.title	In vitro Evidence of Human Immune Responsiveness Shows the Improved Potential of a Recombinant BCG Strain for Bladder Cancer Treatment	en_US
dc.type	Journal Article
utslib.citation.volume	JUN	en_US
utslib.citation.volume	10	en_US
utslib.for	1107 Immunology	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1108 Medical Microbiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	JUN	en_US
pubs.publication-status	Published	en_US
pubs.volume	10	en_US

Abstract:

Copyright © 2019 Rodriguez, Goulart, Pagliarone, Silva, Cunegundes, Nascimento, Borra, Dias, Tagliabue, Boraschi and Leite. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The live attenuated mycobacterial strain BCG, in use as vaccine against tuberculosis, is considered the gold standard for primary therapy of carcinoma in situ of the bladder. Despite its limitations, to date it has not been surpassed by any other treatment. Our group has developed a recombinant BCG strain expressing the detoxified S1 pertussis toxin (rBCG-S1PT) that proved more effective than wild type BCG (WT-BCG) in increasing survival time in an experimental mouse model of bladder cancer, due to the well-known adjuvant properties of pertussis toxin. Here, we investigated the capacity of rBCG-S1PT to stimulate human immune responses, in comparison to WT-BCG, using an in vitro stimulation assay based on human whole blood cells that allows for a comprehensive evaluation of leukocyte activation. Blood leukocytes stimulated with rBCG-S1PT produced increased levels of IL-6, IL-8, and IL-10 as compared to WT-BCG, but comparable levels of IL-1β, IL-2, IFN-γ, and TNF-α. Stimulation of blood cells with the recombinant BCG strain also enhanced the expression of CD25 and CD69 on human CD4+ T cells. PBMC stimulated with rBCG-S1PT induced higher cytotoxicity to MB49 bladder cancer cells than WT-BCG-stimulated PBMC. These results suggest that the rBCG-S1PT strain is able to activate an immune response in human leukocytes that is higher than that induced by WT-BCG for parameters linked to better prognosis in bladder cancer (regulation of immune and early inflammatory responses), while fully comparable to WT-BCG for classical inflammatory parameters. This establishes rBCG-S1PT as a new highly effective candidate as immunotherapeutic agent against bladder cancer.

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http://hdl.handle.net/10453/134329