Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma

Our plain-English summary of Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma, by S. Sun, W. Qi, H. Rehrauer, et al (JTO Clinical and Research Reports, 2022).

The study

• Authors: S. Sun, W. Qi, H. Rehrauer, M. Ronner, A. Hariharan, M. Wipplinger, C. Meiller, R. Stahel, M. Früh, F. Cerciello, J.F. Fonteneau, D. Jean, E. Felley-Bosco
• Journal: JTO Clinical and Research Reports
• Published: 2022;3(12):100430
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: The aim of this study was to investigate endogenous retrovirus (ERV) expression and type I interferon (IFN) activation in human pleural mesothelioma (PM) and their association with clinical outcome.

Methods: The expression of ERV was determined from PM cohorts and mesothelial precursor RNA sequencing data. The expression of ERV was confirmed by quantitative polymerase chain reaction (qPCR). Methylation of genomic DNA was assessed by quantitative methylation-specific PCR. DNA demethylation was induced in cells by demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) treatment. To block type I IFN signaling, the cells were treated with ruxolitinib or MAVS silencing. The expression of IFN-stimulated genes (ISGs) was determined by qPCR and Western blot. Circulating ERVs were detected by qPCR.

Results: Long terminal repeats (LTRs) represent the most abundant transposable elements up-regulated in PM. Within the LTR, ERVmap_1248 and LTR7Y, which are specifically enriched in PM, were further analyzed. The 5-Aza-CdR treatment increased the levels of ERVmap_1248 expression and induced ERVmap_1248 promoter demethylation in mesothelial cells. In addition, ERVmap_1248 promoter was more demethylated in the mesothelioma tissue compared with nontumor tissue. The 5-Aza-CdR treatment of the mesothelial cells also increased the levels of ISGs. Basal ISG expression was higher in the mesothelioma cells compared with the mesothelial cells, and it was significantly decreased by ruxolitinib treatment or MAVS silencing. Furthermore, ISG expression was higher in the tumor tissue with high expression levels of ERVmap_1248. High expression of ERVmap_1248 was associated with longer overall survival and BAP1 mutations. ERVmap_1248 and LTR7Y can be detected in the PM plasma.

Conclusions: We provide clues for patient stratification especially for immunotherapy where best clinical responses are associated with an activated basal immune response.

© 2022 The Authors.

In plain English

This laboratory and patient-sample study examined endogenous retroviruses (ERVs), virus-like sequences in human DNA, in pleural mesothelioma. Asbestos exposure was not measured. The authors compared gene-activity data from two published tumor cohorts and mesothelioma primary cultures with mesothelium grown from human embryonic stem cells, ran cell-line experiments, and tested tumor tissue from 155 patients and plasma from 76 patients and 42 healthy donors. One ERV, ERVmap_1248, was higher in tumor than in nontumor tissue. Its control region was more demethylated (less chemically switched off) in tumors, and a demethylating drug raised it eightfold in mesothelial cells. Tumors with high ERVmap_1248 had higher levels of interferon-related immune genes. Patients in the highest quarter of ERVmap_1248 expression had a median overall survival of 25.16 months, against 13.55 months in the lowest quarter (p = 0.019). ERVmap_1248 was found in the plasma of 13% of patients and of one of 42 healthy donors (2%). The authors concluded that these ERV levels are associated with better clinical outcome and can be detected in blood. They noted that plasma and tumor samples came from different patients.

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 and translational study: analysis of published RNA sequencing data sets, experiments in human mesothelial and pleural mesothelioma cell lines, and testing of patient tumor tissue and plasma, with survival analysis
• Who was studied: Tumor tissue from 155 patients with pleural mesothelioma and nontumor tissue from six non-PM patients, collected 1999 to 2015 (Zurich ethics approval). Plasma from 76 patients with PM enrolled in the SAKK 17/04 trial (2005 to 2012) and from 42 healthy donors (2002 to 2017). RNA sequencing data: TCGA (n = 87) and Bueno study (n = 211) tumor cohorts, FunGeST mesothelioma primary cultures (n = 64), and human embryonic stem cell-derived mesothelium as control (n = 10).
• Exposure: Asbestos exposure was not measured. Asbestos is mentioned only as background, together with the authors' earlier mouse work. The factor studied was expression of endogenous retrovirus sequences, mainly ERVmap_1248 and LTR7Y, in tumors, cells and plasma.
• Main results:
  • In the PM data sets, long terminal repeats (LTRs) were the most abundant transposable elements up-regulated or down-regulated compared with mesothelial precursors.
  • By qPCR, ERVmap_1248 and ERVmap_1064 (but not the control ERVmap_k48) were lower in normal tissue than in tumor tissue.
  • Treating human mesothelial cells (LP9/TERT-1 and SDM104) with the demethylating agent 5-Aza-CdR produced a significant eightfold increase in ERVmap_1248 expression.
  • The ERVmap_1248 promoter was significantly more demethylated in tumor tissues than in nontumor tissues.
  • Interferon-stimulated genes MDA5, RIG-I, STAT1 and ISG15 were higher in most PM cell lines than in mesothelial cells.
  • Ruxolitinib lowered interferon-stimulated gene levels in PM cell lines with an intact IFNB1 gene but not in the IFNB1-deficient line SDM103T2. MAVS silencing also significantly lowered RIG-I, STAT1 and ISG15 in Mero82 and ACC-Meso4 cells.
  • Interferon-stimulated gene expression was higher in patient tumor tissues with high ERVmap_1248 expression.
  • Among the 155 patients split into quarters by ERVmap_1248 expression, median overall survival was 25.16 months in Q4 (highest) versus 13.55 months in Q1 (lowest), hazard ratio 1.57, p = 0.019. It was 24.51 months in Q2 to Q4 combined versus 13.55 months in Q1, hazard ratio 1.761, p = 0.003.
  • In the TCGA data, patients with ERVmap_1248 above the average were enriched for BAP1 mutations but not for NF2 or CDKN2A mutations.
  • Circulating ERVmap_1248 was detected in 13% of plasma samples from PM patients and in one of 42 healthy donor samples (2%).
  • Circulating LTR7Y was detected in 75% of PM patients but also in 24% of healthy controls.
• The authors' conclusion: The authors concluded that mesothelioma-specific ERV levels are associated with a better clinical outcome and can be detected in the blood.
• Limitations the authors state:
  • The plasma samples did not come from the same patients as the tumor samples.
  • Human embryonic stem cell-derived mesothelium was used as the control because RNA sequencing data on normal mesothelial cells or pleura are not available.
  • Relative levels of circulating ERVmap_1248 could not be assessed because the two normalizers used differed in level.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelial Cells, Mesothelioma, Overall Survival, BAP1, Immunotherapy.

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