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

Our plain-English summary of Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response, by C. Achard, N. Boisgerault, T. Delaunay, et al (Oncotarget, 2015).

The study

• Authors: C. Achard, N. Boisgerault, T. Delaunay, D. Roulois, S. Nedellec, P.J. Royer, M. Pain, C. Combredet, M. Mesel-Lemoine, L. Cellerin, A. Magnan, F. Tangy, M. Grégoire, J.F. Fonteneau
• Journal: Oncotarget
• Published: 2015;6(42):44892-904
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study tested the live-attenuated Schwarz vaccine strain of measles virus (MV) in twenty-two human malignant pleural mesothelioma (MPM) cell lines established from pleural effusions and in four types of healthy primary human cells (peritoneal mesothelial, bronchial epithelial, pulmonary endothelial, lung fibroblasts). Using fluorescent recombinant viruses, viability assays, time-lapse microscopy, flow cytometry, RT-qPCR and ELISA, the authors found strong replication and cell death in fifteen of the twenty-two MPM lines and no or very limited replication in the healthy cells. Most MPM lines expressed more CD46 than healthy cells, but CD46 levels did not differ significantly between sensitive and insensitive tumour lines, although blocking CD46 delayed infection. After MV exposure, all healthy cells and all insensitive tumour lines secreted IFN-beta and showed cytoplasmic Mx1, whereas only six of the fifteen sensitive lines secreted IFN-beta and eleven of the fifteen could not express a high level of Mx1. Adding IFN-alpha and IFN-beta reduced MV replication dose-dependently in all fifteen sensitive lines. The authors concluded that MV oncolytic activity exploits defects in the type I interferon response.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro laboratory study of cultured human tumour cell lines and primary healthy cells infected with attenuated measles virus
• Who was studied: Twenty-two human malignant pleural mesothelioma cell lines established in the authors' laboratory from pleural effusions, plus four types of human primary healthy cells (peritoneal mesothelial MES-F, bronchial epithelial CEB, pulmonary endothelial HMVEC-L, lung fibroblasts CCD-19Lu); Nantes, France
• Exposure: Live-attenuated Schwarz vaccine strain measles virus, including recombinant MV-eGFP and MV-ch, at multiplicities of infection of 0.1, 1 and 10; also anti-CD46 blocking antibody and added rhIFN-alpha-2a and rhIFN-beta-1a (10 to 10,000 IU/mL)
• Main results:
  • Fifteen of the twenty-two MPM cell lines supported strong MV replication leading to cell death; seven showed no or low replication
  • In the four healthy primary cell types, no infection (CEB) or very limited infection without syncytia (MES-F, HMVEC-L, CCD-19Lu) was seen
  • Most MPM lines expressed more CD46 than healthy primary cells, but CD46 levels did not differ significantly between MV-sensitive and MV-insensitive tumour lines; CD150 and nectin-4 were not detected
  • Blocking CD46 with a monoclonal antibody delayed MV replication and cell death in seven MV-sensitive lines, with no effect on replication in the insensitive Meso4
  • IFNB1 gene expression was induced by MV in all insensitive tumour cell lines and all healthy cells, but in only seven of the fifteen sensitive lines
  • By ELISA, after MV exposure IFN-beta was secreted by all insensitive lines and all healthy primary cells but by only six of the fifteen sensitive lines; IFN-alpha by all insensitive lines and only four of the fifteen sensitive lines
  • Among the fifteen MV-sensitive lines exposed to MV, six showed no cytoplasmic Mx1, five expressed low levels in a fraction of the cells, and the remainder (Meso34, 36, 37 and 122) expressed high levels in 100% of cells
  • Overall, eleven of the fifteen MV-sensitive lines were unable to express a high level of Mx1 in response to MV
  • Adding IFN-alpha and IFN-beta reduced MV replication dose-dependently in all fifteen sensitive tumour cell lines
  • Counting the two lines in which limited infection triggered apoptosis of neighbouring cells, the authors stated seventeen of twenty-two lines (77%) were sensitive to MV oncolytic activity
• The authors' conclusion: The authors concluded that defects in the type I interferon response are frequent in MPM and that measles virus exploits these defects, with type I IFN defects mattering more than CD46 overexpression
• Limitations the authors state:
  • The authors stated that in vivo confirmation in human MPM tumours engrafted in immunodeficient mice would differ greatly from immunocompetent patients, so an immunocompetent animal model still needs to be developed
  • The authors noted they studied only Mx1 among hundreds of interferon-stimulated genes, and its role in MV replication is not well characterised

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Clinical Trial.

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• Clinical Trials with Oncolytic Measles Virus: Current Status and Future Prospects — P. Msaouel, M. Opyrchal, et al. (2018)
• Reply to: Oncolytic Viral Therapy for Malignant Pleural Mesothelioma — D. Jean, T. Delaunay, et al. (2020)

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