Tlr4-mediated immunomodulatory properties of the bacterial metalloprotease arazyme in preclinical tumor models

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dc.contributor.author Pereira, Felipe V. [UNIFESP]
dc.contributor.author Melo, Amanda C. L. [UNIFESP]
dc.contributor.author de Melo, Filipe M. [UNIFESP]
dc.contributor.author Mourao-Sa, Diego
dc.contributor.author Silva, Priscila [UNIFESP]
dc.contributor.author Berzaghi, Rodrigo [UNIFESP]
dc.contributor.author Herbozo, Carolina C. A. [UNIFESP]
dc.contributor.author Coelho-dos-Reis, Jordana
dc.contributor.author Scutti, Jorge A. [UNIFESP]
dc.contributor.author Origassa, Clarice S. T.
dc.contributor.author Pereira, Rosana M.
dc.contributor.author Juliano, Luis [UNIFESP]
dc.contributor.author Juliano, Maria Aparecida [UNIFESP]
dc.contributor.author Carmona, Adriana K. [UNIFESP]
dc.contributor.author Camara, Niels O. S.
dc.contributor.author Tsuji, Moriya
dc.contributor.author Travassos, Luiz R. [UNIFESP]
dc.contributor.author Rodrigues, Elaine G. [UNIFESP]
dc.date.accessioned 2019-01-21T10:29:46Z
dc.date.available 2019-01-21T10:29:46Z
dc.date.issued 2016
dc.identifier https://doi.org/10.1080/2162402X.2016.1178420
dc.identifier.citation Oncoimmunology. Philadelphia, v. 5, n. 7, p. e1178420, 2016.
dc.identifier.issn 2162-402X
dc.identifier.uri http://repositorio.unifesp.br/handle/11600/49384
dc.description.abstract Despite the recent approval of new agents for metastatic melanoma, its treatment remains challenging. Moreover, few available immunotherapies induce a strong cellular immune response, and selection of the correct immunoadjuvant is crucial for overcoming this obstacle. Here, we studied the immunomodulatory properties of arazyme, a bacterial metalloprotease, which was previously shown to control metastasis in a murine melanoma B16F10-Nex2 model. The antitumor activity of arazyme was independent of its proteolytic activity, since heat-inactivated protease showed comparable properties to the active enzyme en
dc.description.abstract however, the effect was dependent on an intact immune system, as antitumor properties were lost in immunodeficient mice. The protective response was IFN gamma-dependent, and CD8(+) T lymphocytes were the main effector antitumor population, although B and CD4(+) T lymphocytes were also induced. Macrophages and dendritic cells were involved in the induction of the antitumor response, as arazyme activation of these cells increased both the expression of surface activation markers and proinflammatory cytokine secretion through TLR4-MyD88-TRIF-dependent, but also MAPK-dependent pathways. Arazyme was also effective in the murine breast adenocarcinoma 4T1 model, reducing primary and metastatic tumor development, and prolonging survival. To our knowledge, this is the first report of a bacterial metalloprotease interaction with TLR4 and subsequent receptor activation that promotes a proinflammatory and tumor protective response. Our results show that arazyme has immunomodulatory properties, and could be a promising novel alternative for metastatic melanoma treatment. en
dc.description.sponsorship FAPESP
dc.description.sponsorship CAPES
dc.description.sponsorship CNPq
dc.description.sponsorship EGR
dc.description.sponsorship NOCS
dc.description.sponsorship LJ
dc.description.sponsorship MAJ
dc.description.sponsorship ACK
dc.description.sponsorship LRT
dc.format.extent e1178420
dc.language.iso eng
dc.publisher Elsevier Science Inc
dc.relation.ispartof Oncoimmunology
dc.rights Acesso aberto
dc.subject 4t1 en
dc.subject Arazyme en
dc.subject Bacterial Protease en
dc.subject Breast Adenocarcinoma en
dc.subject B16f10 en
dc.subject Immunoadjuvant en
dc.subject Melanoma en
dc.subject Tlr4Melanoma B16f10-Nex2 Cells en
dc.subject Dendritic Cells en
dc.subject Cancer-Immunotherapy en
dc.subject Immune-Response en
dc.subject In-Vivo en
dc.subject Metastatic Melanoma en
dc.subject Antitumor Immunity en
dc.subject Interferon-Gamma en
dc.subject Vaccine Adjuvant en
dc.subject Murine Melanoma en
dc.title Tlr4-mediated immunomodulatory properties of the bacterial metalloprotease arazyme in preclinical tumor models en
dc.type Artigo
dc.description.affiliation Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
dc.description.affiliation Department of Immunology, Instituto de Ci ências Biomédicas (ICB), University of São Paulo (USP), São Paulo, Brazil
dc.description.affiliation HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center (ADARC), Rockefeller University, NY, USA
dc.description.affiliation Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, UK
dc.description.affiliation Rene Rachou Research Center, Oswaldo Cruz Foundation, FIOCRUZ, Minas Gerais, Brazil
dc.description.affiliation Department of Biophysics, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
dc.description.affiliationUnifesp Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFESP), Rua Botucatu 862,8 Andar, BR-04023062 Sao Paulo, SP, Brazil
dc.description.affiliationUnifesp Department of Biophysics, Escola Paulista de Medicina (EPM), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
dc.identifier.doi 10.1080/2162402X.2016.1178420
dc.description.source Web of Science
dc.identifier.wos WOS:000385486700021



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