Please use this identifier to cite or link to this item: http://repositorio.unifesp.br/handle/11600/49384
Title: Tlr4-mediated immunomodulatory properties of the bacterial metalloprotease arazyme in preclinical tumor models
Authors: Pereira, Felipe V. [UNIFESP]
Melo, Amanda C. L. [UNIFESP]
de Melo, Filipe M. [UNIFESP]
Mourao-Sa, Diego
Silva, Priscila [UNIFESP]
Berzaghi, Rodrigo [UNIFESP]
Herbozo, Carolina C. A. [UNIFESP]
Coelho-dos-Reis, Jordana
Scutti, Jorge A. [UNIFESP]
Origassa, Clarice S. T.
Pereira, Rosana M.
Juliano, Luis [UNIFESP]
Juliano, Maria Aparecida [UNIFESP]
Carmona, Adriana K. [UNIFESP]
Camara, Niels O. S.
Tsuji, Moriya
Travassos, Luiz R. [UNIFESP]
Rodrigues, Elaine G. [UNIFESP]
Keywords: 4t1
Arazyme
Bacterial Protease
Breast Adenocarcinoma
B16f10
Immunoadjuvant
Melanoma
Tlr4Melanoma B16f10-Nex2 Cells
Dendritic Cells
Cancer-Immunotherapy
Immune-Response
In-Vivo
Metastatic Melanoma
Antitumor Immunity
Interferon-Gamma
Vaccine Adjuvant
Murine Melanoma
Issue Date: 2016
Publisher: Elsevier Science Inc
Citation: Oncoimmunology. Philadelphia, v. 5, n. 7, p. e1178420, 2016.
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.
URI: http://repositorio.unifesp.br/handle/11600/49384
ISSN: 2162-402X
Other Identifiers: https://doi.org/10.1080/2162402X.2016.1178420
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