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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

Tiphaine Delaunay 1 Carole Achard 1 Nicolas Boisgerault 1 Marion Grard 1 Tacien Petithomme 1 Camille Chatelain 1 Soizic Dutoit 1 Christophe Blanquart 1 Pierre-Joseph Royer 2 Stéphane Minvielle 3 Lisa Quetel 4 Clément Meiller 4 Didier Jean 4 Delphine Fradin 1 Jaafar Bennouna 1, 5 Antoine Magnan 2, 6 Laurent Cellerin 6 Frédéric Tangy 7 Marc Grégoire 1 Jean-François Fonteneau 1, *
* Corresponding author
1 CRCINA-ÉQUIPE 4 - Immunogenic Cell Death and Mesothelioma Therapy
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
2 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291
3 CRCINA-ÉQUIPE 11 - Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
4 U1162 - Génomique Fonctionnelle des Tumeurs Solides
5 Service d'Oncologie Médicale Thoracique et Digestive [CHU Nantes]
6 Service de pneumologie [Nantes]
7 EPVO (UMR_3569 / U-Pasteur_3) - Epidémiologie et Physiopathologie des Virus Oncogènes
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.
Keywords : mesothelioma gene homozygous deletion Oncolytic immunotherapy measles virus type I interferon
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INSERM | CRCINA | UNIV-NANTES | UNIV-PARIS13 | THORAX-UMR | UNIV-ANGERS | USPC | CNRS | PASTEUR | UNIV-PARIS | UP-SCIENCES

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Tiphaine Delaunay, Carole Achard, Nicolas Boisgerault, Marion Grard, Tacien Petithomme, et al.. 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. Journal of Thoracic Oncology, Lippincott, Williams & Wilkins, 2020, S1556-0864(20)30019-8, Epub ahead of print. ⟨10.1016/j.jtho.2019.12.128⟩. ⟨inserm-02447160⟩

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