Efeito imunomodulador da metaloprotease bacteriana oligopeptidase A no tratamento do melanoma murino B16F10-NEX2
Data
2022
Autores
Silva, Gabrielli Novaes 
Orientadores
Rodrigues, Elaine Guadelupe
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Nos últimos anos houve um aumento significativo na incidência do melanoma. As terapias disponíveis atualmente contra essa doença, infelizmente, não aumentam significativamente a sobrevida dos pacientes, e, portanto, novas alternativas terapêuticas são necessárias. Fatores imunossupressores presentes no microambiente tumoral fazem com que a resposta imune antitumoral não seja efetiva, além de também reduzirem a eficácia das imunoterapias antitumorais já em uso atualmente. Imunomoduladores são alternativas atraentes para a neutralização da imunossupressão do microambiente tumoral, através da ativação de efetores da resposta imune. Estudos realizados com diferentes proteases demonstraram que estas são capazes de ativar células do sistema imune. Nosso grupo demonstrou que metaloproteases, tanto de origem bacteriana como eucariótica, quando utilizadas para o tratamento in vivo do melanoma murino B16F10-Nex2, reduzem significativamente o crescimento desse modelo tumoral, pela modulação do sistema imunológico. A arazima, de origem bacteriana, e a thimet oligopeptidase (TOP) clonada a partir de células murinas, foram capazes de ativar células do sistema imune, mesmo em sua forma inativa, através da interação com o receptor TLR-4 e sinalização dependente da via Myd88/TRIF/MAPK, e inibir o desenvolvimento do melanoma murino através de uma resposta dependente de linfócitos T e interferon-. Estudo anterior do nosso grupo demonstrou que a Oligopeptidase A (Opda), uma outra metaloprotease bacteriana, também reduziu significativamente o número de nódulos metastáticos pulmonares. A OpdA foi capaz de ativar células dendríticas in vitro, aumentando a produção de citocinas pró-inflamatórias, óxido nítrico, e, também, a expressão de moléculas coestimuladoras na superfície celular, em efeito independente de sua atividade proteolítica, e também pela interação com TLR-4 e de vias de sinalização dependentes de MyD88/TRIF. Neste trabalho, complementando os estudos com a OpdA, mostramos que o efeito antitumoral da OpdA depende de linfócitos T CD4+ e CD8+ tumor-específicos, e do IFN- induzido pelo tratamento com a metaloprotease.
In recent years there has been a significant increase in the incidence of melanoma. The therapies currently available against this disease, unfortunately, do not significantly increase patient survival, and therefore, new therapeutic alternatives are needed. Immunosuppressive factors present in the tumor microenvironment impairs the antitumor immune response in addition to reducing the effectiveness of anti-tumor immunotherapies already in use today. Immunomodulators are attractive alternatives for neutralizing the immunosuppression of the tumor microenvironment, by activating effectors of the immune response. Studies carried out with different proteases have shown that some of them are able to activate cells of the immune system. Our group demonstrated that metalloproteases, both bacterial and eukaryotic, when used for the in vivo treatment of murine melanoma B16F10-Nex2, significantly reduce the growth of this tumor model, by modulating the immune system. Arazyme of bacterial origin, and thimet oligopeptidase (TOP) cloned from murine cells, were able to activate cells of the immune system, even in their inactive form, through interaction with the TLR-4 receptor and Myd88/TRIF/MAPK pathway-dependent signaling, inducing a T-lymphocyte- and interferon--dependent tumor response. A previous study by our group showed that Oligopeptidase A (Opda), a bacterial metalloprotease obtained from a different microorganism, also significantly reduced the number of pulmonary metastatic nodules. OpdA was able to activate dendritic cells (DC) in vitro, increasing the production of pro-inflammatory cytokines, nitric oxide, and also the expression of costimulatory molecules on DC surface. This effect was independent of its proteolytic activity, but dependent on the interaction with TLR-4 and MyD88 / TRIF signaling pathways. In this work, complementing the studies with OpdA, we show that the antitumor effect of OpdA depends on tumor-specific CD4+ and CD8+ T lymphocytes, and on IFN- induced by treatment with metalloprotease.
In recent years there has been a significant increase in the incidence of melanoma. The therapies currently available against this disease, unfortunately, do not significantly increase patient survival, and therefore, new therapeutic alternatives are needed. Immunosuppressive factors present in the tumor microenvironment impairs the antitumor immune response in addition to reducing the effectiveness of anti-tumor immunotherapies already in use today. Immunomodulators are attractive alternatives for neutralizing the immunosuppression of the tumor microenvironment, by activating effectors of the immune response. Studies carried out with different proteases have shown that some of them are able to activate cells of the immune system. Our group demonstrated that metalloproteases, both bacterial and eukaryotic, when used for the in vivo treatment of murine melanoma B16F10-Nex2, significantly reduce the growth of this tumor model, by modulating the immune system. Arazyme of bacterial origin, and thimet oligopeptidase (TOP) cloned from murine cells, were able to activate cells of the immune system, even in their inactive form, through interaction with the TLR-4 receptor and Myd88/TRIF/MAPK pathway-dependent signaling, inducing a T-lymphocyte- and interferon--dependent tumor response. A previous study by our group showed that Oligopeptidase A (Opda), a bacterial metalloprotease obtained from a different microorganism, also significantly reduced the number of pulmonary metastatic nodules. OpdA was able to activate dendritic cells (DC) in vitro, increasing the production of pro-inflammatory cytokines, nitric oxide, and also the expression of costimulatory molecules on DC surface. This effect was independent of its proteolytic activity, but dependent on the interaction with TLR-4 and MyD88 / TRIF signaling pathways. In this work, complementing the studies with OpdA, we show that the antitumor effect of OpdA depends on tumor-specific CD4+ and CD8+ T lymphocytes, and on IFN- induced by treatment with metalloprotease.