Oncolytic activity of attenuated Measles virus and the defects in the type I interferon response in cancer

Anti-tumor virotherapy is based on non-pathogenic replicative oncolytic viruses (OV). OVs specifically lyze tumor cells, which stimulates the anti-tumor immune response. This therapeutic strategy is developing fast since the approval by EMA and FDA of the T-vec, an oncolytic herpes virus for the treatment of metastatic melanoma.
 In collaboration with Dr Frédéric Tangy from Pasteur Institute, Paris, our team studies the spontaneous oncolytic activity of attenuated measles (MV) against several cancers, especially malignant pleural mesothelioma (MPM). We recently showed that the sensitivity of tumor cells to MV oncolytic activity is due to defects in their intracellular antiviral type I interferon (IFN I) response. In MPM, we showed that the most frequent defect (about 20% of patients) is the homozygous deletion of the genes encoding IFN I (IFNB1 and IFNA). These genes are co-deleted with the tumor suppressor gene CDKN2A that is located on the same p21.3 region of chromosome 9. By an analysis of the “The Cancer Genome Atlas”, we show that deletions of the IFN I genes are frequent in all cancers where deletions of CDKN2A are implicated, such as glioblastoma or lung adenocarcinoma. We also showed that MV induces immunogenic death of sensitive MPM cell lines that develop a pro-inflammatory response and a shock of the endoplasmic reticulum before to die. In addition, we observed that tumor antigens released during tumor cell death can be captured and cross-presented by antigen presenting cells such as dendritic cells. More recently, we also showed that these released tumor antigens can also reinforce tumor antigen presentation by the tumor cells themselves. Finally, we study MVC, a modified MV that is unable to express the viral C protein. We demonstrated that MVC develops a faster oncolytic activity and induces a stronger immunogenic cell death.
Altogether, our studies identify MV and MVC as interesting OVs to target tumor cells with defects in the IFN I response.

Jean-François Fonteneau, CRCINA, INSERM U1232, Labex IGO, Siric ILIAD, Nantes

During his PhD, Jean-François Fonteneau studied T cells response against melanoma in Pr Jotereau lab, Nantes, France (1996-99). He joined Dr Bhardwaj in Dr Steinman Lab at Rockefeller University (1999-2003), where he studied DC biology, notably cross-presentation of viral and tumor Ag. He returned to Pr Jotereau Lab to identify melanoma Ag recognised by patients T cells (2003-08). In 2009, he joined Dr Gregoire Lab, INSERM U892, to study attenuated measles virus as an oncolytic virus for virotherapy of pleural mesothelioma.