Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma

Suna Sun; Weihong Qi; Hubert Rehrauer; Manuel Ronner; Ananya Hariharan; Martin Wipplinger; Clément Meiller; Rolf Stahel; Martin Früh; Ferdinando Cerciello; Jean-François Fonteneau; Didier Jean; Emanuela Felley-Bosco

doi:10.1016/j.jtocrr.2022.100430

Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma

JTO Clin Res Rep. 2022 Nov 7;3(12):100430. doi: 10.1016/j.jtocrr.2022.100430. eCollection 2022 Dec.

Authors

Affiliations

¹ Laboratory of Molecular Oncology, Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
² Functional Genomics Center, ETH Zurich, University of Zurich, Zurich, Switzerland.
³ Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, Université Paris Cité, Functional Genomics of Solid Tumors, Paris, France.
⁴ Coordinating Center, European Thoracic Oncology Platform (ETOP), Bern, Switzerland.
⁵ Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
⁶ Department of Medical Oncology/Hematology, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland.
⁷ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁸ Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France.

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.

Keywords: BRCA-associated protein 1; Endogenous retroviruses; Pleural mesothelioma; Type I interferon.