Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus

Our plain-English summary of Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus, by T. Delaunay, C. Achard, N. Boisgerault, et al (Journal of Thoracic Oncology, 2020).

The study

• Authors: T. Delaunay, C. Achard, N. Boisgerault, M. Grard, T. Petithomme, C. Chatelain, S. Dutoit, C. Blanquart, P.J. Royer, S. Minvielle, L. Quetel, C. Meiller, D. Jean, D. Fradin, J. Bennouna, A. Magnan, L. Cellerin, F. Tangy, M. Grégoire, J.F. Fonteneau
• Journal: Journal of Thoracic Oncology
• Published: 2020;15(5):827-842
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Oncolytic immunotherapy is based on the use of nonpathogenic replicative oncolytic viruses that infect and kill tumor cells exclusively. Recently, we found that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN-I) response in tumor cells.

Methods: In this study, we studied three independent human MPM bio-collections to identify the defects in the IFN-I responses in tumor cells.

Results: We show that the most frequent defect is the homozygous deletions (HDs) of all the 14 IFN-I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HDs occur together with the HDs of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN-I-/- MPM cell lines develop a partial and weak IFN-I response when they are exposed to the virus compared with that of normal cells and MV-resistant MPM cell lines. This response consists of the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN-I. In addition, the IFN-I-/- MPM cell lines infected by MV also develop a pro-inflammatory response associated with stress of the endoplasmic reticulum.

Conclusion: Our study emphasizes the link between HDs of IFN-I encoding genes and the CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.

Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study investigated why some human malignant pleural mesothelioma (MPM) cell lines are killed by the attenuated Schwarz strain of measles virus (MV); the introduction describes MPM as often resulting from long-term asbestos exposure. The authors worked with MPM cell lines established from pleural effusions, a validation series of 78 short-term-cultured MPM cell lines, healthy primary cells and public tumour genome data, testing viral replication, gene copy number and gene expression. Genomic PCR showed that eight of the 15 MV-sensitive cell lines had lost both copies of IFNB1; a separate genomic array analysis of those eight lines showed the deletion also covered the interferon-alpha genes and extended past CDKN2A on chromosome 9p21.3. In the 78-line series, 57 of 78 (73%) had lost CDKN2A and 18 of 78 (23%) IFNB1. Cells lacking type I interferon genes mounted only a partial interferon response to MV, together with inflammatory and endoplasmic reticulum stress responses. The authors concluded that sensitivity to oncolytic measles virus is often caused by these deletions; seven of the 15 sensitive lines retained at least one IFNB1 copy.

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: Laboratory (in vitro) study of human mesothelioma and other cell lines, combining virus infection experiments, genomic PCR and arrays, transcriptomics, Western blotting, gene editing and public database analysis
• Who was studied: Human MPM cell lines established in the authors' laboratory from pleural effusions (Meso 4 to Meso 225; 22 lines, 15 MV-sensitive and MV-resistant lines tested), a validation series of 78 short-term-cultured MPM cell lines from INSERM U1162, Paris, four types of healthy primary human cells, 11 lung cancer cell lines, and TCGA data on 87 patients with MPM
• Exposure: Infection of cells with the live-attenuated Schwarz vaccine strain of measles virus (including cherry-fluorescent recombinant MV) at multiplicity of infection of 1 or 10, with or without treatment with recombinant type I interferons (rhIFN-alpha2a and rhIFN-beta1a, 1000 IU/mL) or the JAK inhibitor ruxolitinib (1 microM)
• Main results:
  • Among the laboratory's cell lines, genomic PCR showed eight of the 15 MV-sensitive MPM cell lines had a homozygous deletion of IFNB1, while six MV-resistant and seven MV-sensitive lines kept at least one copy
  • A separate genomic array (Cytoscan) analysis was performed on the eight IFNB1-deleted lines and four MV-resistant lines to measure the size of the chromosome 9 deletions
  • In the eight MV-sensitive lines studied by genomic array, the deletion ran from the IFNB1 position across the IFN-alpha genes and beyond CDKN2A
  • In the validation series of 78 short-term-cultured MPM cell lines, homozygous deletion of CDKN2A was found in 57 of 78 (73%) and of IFNB1 in 18 of 78 (23%)
  • Of the 78 lines, 17 of the 18 that had lost IFNB1 (94%) had also lost CDKN2A, and one line (MPM_51) lost only IFNB1
  • In the 78-line series, IFNB1 homozygous deletion was reported as significantly more frequent in MPM with a sarcomatoid component (Fisher's exact test, p = 0.0085)
  • By histological type in the 78-line series: 17% of epithelioid, 45% of biphasic and 50% of sarcomatoid or desmoplastic MPM carried the IFNB1 deletion
  • In TCGA data on 87 patients with MPM, homozygous deletions were seen for CDKN2A in 43.8%, IFNA2 in 18.4% and IFNB1 in 9.2%
  • Knocking out IFNB1 made only one of the four MV-resistant lines (Meso 45) permissive to viral replication; restoring IFNB1 strongly reduced replication in four of five interferon-deleted lines and moderately in Meso 163
  • Interferon-gene-deleted MPM cell lines exposed to MV expressed only a limited set of interferon-stimulated genes (RSAD2, IFIT1, OAS1, DDX58) and failed to express others (XAF1, TLR3, STAT1, MX1) unless given exogenous interferon
  • Pathway analysis showed that, in the interferon-gene-deleted lines only, MV also activated inflammatory and endoplasmic reticulum stress pathways
• The authors' conclusion: The authors concluded that sensitivity of human MPM cells to attenuated measles virus is often caused by homozygous deletion of the type I interferon genes, occurring together with CDKN2A deletion, and that these deletions represent a therapeutic target for oncolytic measles virus
• Limitations the authors state:
  • The authors noted that most of their own cell lines had been passaged more than 10 times, raising the possibility of a culture bias in which CDKN2A-deleted lines are easier to establish
  • The authors considered the TCGA deletion frequencies likely to be underestimates because sequencing of tumour biopsies includes healthy cells that can mask deletions present only in tumour cells
  • The authors stated that homozygous deletion of interferon genes is not the only defect: seven of the 15 MV-sensitive lines retained at least one IFNB1 copy
  • Attempts to measure induction of IRF3, IRF7 and RELA expression at 12 or 24 hours after MV exposure were unsuccessful and the data are not shown

Topics

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

Medical terms in this study, explained in our Lexicon: Homozygous Deletion, Pleural Mesothelioma, Immunotherapy, Tumor Suppressor Gene, CDKN2A.

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