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

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

Author Pereira, Felipe V. Autor UNIFESP Google Scholar
Melo, Amanda C. L. Autor UNIFESP Google Scholar
de Melo, Filipe M. Autor UNIFESP Google Scholar
Mourao-Sa, Diego Google Scholar
Silva, Priscila Autor UNIFESP Google Scholar
Berzaghi, Rodrigo Autor UNIFESP Google Scholar
Herbozo, Carolina C. A. Autor UNIFESP Google Scholar
Coelho-dos-Reis, Jordana Google Scholar
Scutti, Jorge A. Autor UNIFESP Google Scholar
Origassa, Clarice S. T. Google Scholar
Pereira, Rosana M. Google Scholar
Juliano, Luis Autor UNIFESP Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Carmona, Adriana K. Autor UNIFESP Google Scholar
Camara, Niels O. S. Google Scholar
Tsuji, Moriya Google Scholar
Travassos, Luiz R. Autor UNIFESP Google Scholar
Rodrigues, Elaine G. Autor UNIFESP Google Scholar
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

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.
Keywords 4t1
Bacterial Protease
Breast Adenocarcinoma
Tlr4Melanoma B16f10-Nex2 Cells
Dendritic Cells
Metastatic Melanoma
Antitumor Immunity
Vaccine Adjuvant
Murine Melanoma
Language English
Sponsor FAPESP
Date 2016
Published in Oncoimmunology. Philadelphia, v. 5, n. 7, p. e1178420, 2016.
ISSN 2162-402X (Sherpa/Romeo, impact factor)
Publisher Elsevier Science Inc
Extent e1178420
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000385486700021

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