RESUMO
The Bacillus Calmette-Guérin (BCG) vaccine is the oldest cancer immunotherapeutic agent in use. Despite its effectiveness, its initial mechanisms of action remain largely unknown. Here, we elucidate the earliest cellular mechanisms involved in BCG-induced tumor clearance. We developed a fast preclinical in vivo assay to visualize in real time and at single-cell resolution the initial interactions among bladder cancer cells, BCG and innate immunity using the zebrafish xenograft model. We show that BCG induced the recruitment and polarization of macrophages towards a pro-inflammatory phenotype, accompanied by induction of the inflammatory cytokines tnfa, il1b and il6 in the tumor microenvironment. Macrophages directly induced apoptosis of human cancer cells through zebrafish TNF signaling. Macrophages were crucial for this response as their depletion completely abrogated the BCG-induced phenotype. Contrary to the general concept that macrophage anti-tumoral activities mostly rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can induce tumor apoptosis and clearance. Thus, our results revealed an additional step to the BCG-induced tumor immunity model, while providing proof-of-concept experiments demonstrating the potential of this unique model to test innate immunomodulators.
Assuntos
Apoptose , Vacina BCG , Macrófagos , Transdução de Sinais , Neoplasias da Bexiga Urinária , Peixe-Zebra , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Animais , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Vacina BCG/farmacologia , Vacina BCG/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Humanos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Microambiente TumoralRESUMO
Latent tuberculosis was studied in a research laboratory. A prevalence of positive tuberculin skin test results (>or= 15 mm) of 20% was found and the main predictors were place of birth in a foreign country with high prevalence of tuberculosis and a history of contact with patients with untreated active tuberculosis.
Assuntos
Pessoal de Laboratório Médico/estatística & dados numéricos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/epidemiologia , Adulto , Feminino , Pessoal Profissional Estrangeiro , Humanos , Transmissão de Doença Infecciosa do Paciente para o Profissional , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Teste Tuberculínico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/transmissão , Adulto JovemRESUMO
Latent tuberculosis was studied in a research laboratory. A prevalence of positive tuberculin skin test results (> 15mm) of 20 percent was found and the main predictors were place of birth in a foreign country with high prevalence of tuberculosis and a history of contact with patients with untreated active tuberculosis.
A tuberculose latente foi estudada em um laboratório de investigação. Foi encontrada uma prevalência de 20 por cento de resultados positivos para o teste cutâneo de tuberculina (> 15mm) e os principais fatores preditores foram ser natural de um país estrangeiro com alta prevalência de tuberculose e ter uma história de contato com doentes com tuberculose ativa não tratada.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Pessoal de Laboratório/estatística & dados numéricos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/epidemiologia , Pessoal Profissional Estrangeiro , Transmissão de Doença Infecciosa do Paciente para o Profissional , Prevalência , Fatores de Risco , Teste Tuberculínico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/transmissão , Adulto JovemRESUMO
Immunity to intracellular bacteria including Mycobacterium tuberculosis. Mycobacterium leprae, and Listeria monocytogenes depends on specific T cells. Evidence to be described suggests that CD4 (alpha/beta)T cells which interact with each other and with macrophages contribute to acquired resistence against as well as pathogenesis of intracellular bacterial infections