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Cancer Res ; 68(12): 4882-92, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18559536

RESUMO

Despite conventional medical and surgical treatments, malignant pleural mesothelioma (MPM) remains incurable. Oncovirotherapy (i.e., the use of replication-competent virus for cancer treatment) is currently explored in clinical trials. In this study, we investigated the antineoplastic potential of a new oncolytic viral agent, a live-attenuated measles virus (MV) strain derived from the Edmonston vaccine lineage (Schwarz strain). We evaluated both oncolytic activity and immunoadjuvant properties of the MV vaccine strain on mesothelioma tumor cells. Infectivity, syncytium formation, and cytolytic activity of MV were studied on a panel of mesothelioma cells derived from pleural effusions of MPM patients. We observed that MV infected preferentially MPM cell lines in comparison with nontransformed mesothelial cells, leading to an efficient killing of a significant fraction of tumor cells. A cytoreductive activity was also evidenced through formation of multinuclear cellular aggregates (syncytia). The susceptibility of MPM cell lines to measles infection was assessed by the analysis of cell surface expression of the MV vaccine receptor (CD46). We also evaluated whether MV infection of mesothelioma cells could elicit an autologous antitumor immune response. We showed that MV Schwarz strain induced apoptotic cell death of infected mesothelioma cells, which were efficiently phagocytosed by dendritic cells (DC). Loading of DCs with MV-infected MPM cells induced DC spontaneous maturation, as evidenced by the increased expression of MHC and costimulatory molecules along with the production of proinflammatory cytokines. Priming of autologous T cells by DCs loaded with MV-infected MPM cells led to a significant proliferation of tumor-specific CD8 T cells. Altogether, these data strongly support the potential of oncolytic MV as an efficient therapeutic agent for mesothelioma cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Vírus do Sarampo/genética , Sarampo/imunologia , Mesotelioma/terapia , Mesotelioma/virologia , Terapia Viral Oncolítica , Derrame Pleural Maligno/imunologia , Animais , Apoptose , Chlorocebus aethiops , Apresentação Cruzada , Efeito Citopatogênico Viral , Células Dendríticas/patologia , Células Dendríticas/virologia , Humanos , Sarampo/patologia , Sarampo/virologia , Vírus do Sarampo/imunologia , Proteína Cofatora de Membrana/metabolismo , Mesotelioma/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Fagocitose , Derrame Pleural Maligno/patologia , Derrame Pleural Maligno/virologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Células Vero , Ensaios Antitumorais Modelo de Xenoenxerto
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