Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus: Interferon genes loss sensitizes tumor cells to viral lysis

Abstract : Oncolytic immunotherapy is based on the use of non-pathogenic replicative oncolytic viruses (OV) that infect and kill exclusively tumor cells. Recently, we showed 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. In this study, we identify the most frequent defect as the homozygous deletions (HD) of all fourteen IFN I genes (IFN- and IFN-) that we found in more than half of MV-sensitive MPM cell lines. These HD occur together with the HD 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 to normal cells and MV-resistant MPM cell lines. This response consists in 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 a stress of the endoplasmic reticulum. Our study emphasizes the link between HD of IFN I encoding genes and CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.