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
Type de document :
Article dans une revue
Oncotarget, Impact journals, 2015, 6 (42), pp.44892-44904. 〈10.18632/oncotarget.6285〉
Liste complète des métadonnées

Littérature citée [36 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-01285131
Contributeur : Elizabeth Bernardo <>
Soumis le : mardi 8 mars 2016 - 16:19:05
Dernière modification le : mardi 2 octobre 2018 - 11:26:02

Fichier

2015-C ACHARD-Oncotarget.pdf
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

Citation

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〉

Partager

Métriques

Consultations de la notice

249

Téléchargements de fichiers

74