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Published on: October 2, 2015
Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma
Suna Sun1, Weihong Qi2, Hubert Rehrauer2
1Laboratory of Molecular Oncology, Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
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.
Insights
Endogenous retrovirus (ERV) expression, particularly ERVmap_1248, is elevated in pleural mesothelioma and linked to better survival. This ERV activation correlates with type I interferon signaling, suggesting potential for immunotherapy patient stratification.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Endogenous retroviruses (ERVs) are remnants of ancient viral infections integrated into the host genome.
- Their aberrant expression is implicated in various cancers, including pleural mesothelioma (PM).
- Type I interferon (IFN) signaling plays a crucial role in antiviral defense and immune surveillance.
Purpose of the Study:
- To investigate endogenous retrovirus (ERV) expression and type I interferon (IFN) activation in human pleural mesothelioma (PM).
- To determine the association between ERV expression, IFN activation, and clinical outcomes in PM patients.
- To explore the potential of ERVs as biomarkers for patient stratification, particularly for immunotherapy.
Main Methods:
- Quantification of ERV expression using RNA sequencing and quantitative polymerase chain reaction (qPCR) in PM cohorts and mesothelial cells.
- Assessment of DNA methylation status of ERV promoters using quantitative methylation-specific PCR.
- Experimental manipulation of ERV expression and IFN signaling pathways using demethylating agents (5-Aza-CdR), ruxolitinib, and MAVS silencing.
- Detection of circulating ERVs in plasma samples from PM patients.
Main Results:
- Long terminal repeats (LTRs), specifically ERVmap_1248 and LTR7Y, were significantly upregulated in PM.
- ERVmap_1248 expression and promoter demethylation were induced by 5-Aza-CdR in mesothelial cells and were higher in mesothelioma tissue.
- Increased ERVmap_1248 expression correlated with higher IFN-stimulated gene (ISG) levels, longer overall survival, and BAP1 mutations.
- ERVmap_1248 and LTR7Y were detectable in PM patient plasma.
Conclusions:
- Aberrant ERV expression, particularly ERVmap_1248, is a feature of pleural mesothelioma.
- ERVmap_1248 upregulation is linked to an activated type I IFN response and favorable clinical outcomes.
- These findings suggest ERVs could serve as biomarkers for patient stratification in PM, potentially guiding immunotherapy strategies.
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