Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.
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ICR Authors
Authors
Wedge, M-E
Jennings, VA
Crupi, MJF
Poutou, J
Jamieson, T
Pelin, A
Pugliese, G
de Souza, CT
Petryk, J
Laight, BJ
Boileau, M
Taha, Z
Alluqmani, N
McKay, HE
Pikor, L
Khan, ST
Azad, T
Rezaei, R
Austin, B
He, X
Mansfield, D
Rose, E
Brown, EEF
Crawford, N
Alkayyal, A
Surendran, A
Singaravelu, R
Roy, DG
Migneco, G
McSweeney, B
Cottee, ML
Jacobus, EJ
Keller, BA
Yamaguchi, TN
Boutros, PC
Geoffrion, M
Rayner, KJ
Chatterjee, A
Auer, RC
Diallo, J-S
Gibbings, D
tenOever, BR
Melcher, A
Bell, JC
Ilkow, CS
Jennings, VA
Crupi, MJF
Poutou, J
Jamieson, T
Pelin, A
Pugliese, G
de Souza, CT
Petryk, J
Laight, BJ
Boileau, M
Taha, Z
Alluqmani, N
McKay, HE
Pikor, L
Khan, ST
Azad, T
Rezaei, R
Austin, B
He, X
Mansfield, D
Rose, E
Brown, EEF
Crawford, N
Alkayyal, A
Surendran, A
Singaravelu, R
Roy, DG
Migneco, G
McSweeney, B
Cottee, ML
Jacobus, EJ
Keller, BA
Yamaguchi, TN
Boutros, PC
Geoffrion, M
Rayner, KJ
Chatterjee, A
Auer, RC
Diallo, J-S
Gibbings, D
tenOever, BR
Melcher, A
Bell, JC
Ilkow, CS
Document Type
Journal Article
Date
2022-04-07
Date Accepted
2022-03-07
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 VSVĪ51 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.
Citation
Nature Communications, 2022, 13 (1), pp. 1898 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Trans Immunotherapy