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Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response

Abstract : Attenuated measles virus (MV) is currently being evaluated as an oncolytic virus in clinical trials and could represent a new therapeutic approach for malignant pleural mesothelioma (MPM). Herein, we screened the sensitivity to MV infection and replication of twenty-two human MPM cell lines and some healthy primary cells. We show that MV replicates in fifteen of the twenty-two MPM cell lines. Despite overexpression of CD46 by a majority of MPM cell lines compared to healthy cells, we found that the sensitivity to MV replication did not correlate with this overexpression. We then evaluated the antiviral type I interferon (IFN) responses of MPM cell lines and healthy cells. We found that healthy cells and the seven insensitive MPM cell lines developed a type I IFN response in presence of the virus, thereby inhibiting replication. In contrast, eleven of the fifteen sensitive MPM cell lines were unable to develop a complete type I IFN response in presence of MV. Finally, we show that addition of type I IFN onto MV sensitive tumor cell lines inhibits replication. These results demonstrate that defects in type I IFN response are frequent in MPM and that MV takes advantage of these defects to exert oncolytic activity. INTRODUCTION Antitumor virotherapy using oncolytic viruses is a developing strategy to treat cancer [1]. Among oncolytic viruses, attenuated strains of measles virus (MV) have been shown to infect and kill a large variety of tumor cell lines [2, 3]. Phase I clinical trials using the Edmonston strain of MV have shown clinical benefits for the treatment of cutaneous T cell lymphoma [4], ovarian cancer [5, 6] and disseminated multiple myeloma [1]. The Edmonston MV is also currently being evaluated in ongoing phase I clinical trials for the treatment of squamous cell carcinoma of the head and the neck, glioma and mesothelioma by the group of Stephen J. Russell at the Mayo Clinic [1]. Schwarz and Edmonston attenuated strains of MV use the CD46 molecule as the major receptor to infect human cells, unlike the pathogenic strains that mainly use the CD150 molecule [7-9]. The membrane cofactor protein CD46 is ubiquitously expressed at a low level by all nucleated cells and blocks the complement cascade at the C3 activation stage [10]. CD46 is often overexpressed on tumor cells of many cancer types to escape complement
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Carole Achard, Nicolas Boisgerault, Tiphaine Delaunay, David Roulois, Steven Nedellec, et al.. Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response. Oncotarget, Impact journals, 2015, 6 (42), pp.44892-44904. ⟨10.18632/oncotarget.6285⟩. ⟨inserm-01285131⟩



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