Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy
Marie-Ève Wedge, Victoria A. Jennings, Mathieu J. F. Crupi, Joanna Poutou, Taylor R. Jamieson, Adrian Pelin, Giuseppe Pugliese, Christiano Tanese de Souza, Julia Petryk, Brian J. Laight, Meaghan Boileau, Zaid Taha, Nouf Alluqmani, Hayley E. McKay, Larissa A. Pikor, S. Khan, Taha Azad, Reza Rezaei, Bradley Austin, Xiaohong He, David Mansfield, Elaine G Rose, Emily E. F. Brown, Natalie D. Crawford, Almohanad A. Alkayyal, Abera Surendran, Ragunath Singaravelu, Dominic G. Roy, G Migneco, Benjamin McSweeney, Mary Lynn Cottee, Egon J. Jacobus, Brian A. Keller, Takafumi N. Yamaguchi, Paul C. Boutros, Michèle Geoffrion, Katey J. Rayner, Avijit Chatterjee, Rebecca C. Auer, Jean‐Simon Diallo, Derrick Gibbings, Benjamin R. tenOever, Alan Melcher, John C. Bell, Carolina S. Ilkow
Abstract
Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or "cancer-killing" viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.