Maraba MG1 virus enhances natural killer cell function via conventional dendritic cells to reduce postoperative metastatic disease.
This study characterizes the ability of novel oncolytic rhabdoviruses (Maraba MG1) to boost natural killer (NK) cell activity. Our results demonstrate that MG1 activates NK cells via direct infection and maturation of conventional dendritic cells. Using NK depletion and conventional dendritic cells ablation studies in vivo, we established that both are required for MG1 efficacy. We further explored the efficacy of attenuated MG1 (nonreplicating MG1-UV(2min) and single-cycle replicating MG1-Gless) and demonstrated that these viruses activate conventional dendritic cells, although to a lesser extent than live MG1. This translates to equivalent abilities to remove tumor metastases only at the highest viral doses of attenuated MG1. In tandem, we characterized the antitumor ability of NK cells following preoperative administration of live and attenuated MG1. Our results demonstrates that a similar level of NK activation and reduction in postoperative tumor metastases was achieved with equivalent high viral doses concluding that viral replication is important, but not necessary for NK activation. Biochemical characterization of a panel of UV-inactivated MG1 (2-120 minutes) revealed that intact viral particle and target cell recognition are essential for NK cell-mediated antitumor responses. These findings provide mechanistic insight and preclinical rationale for safe perioperative virotherapy to effectively reduce metastatic disease following cancer surgery.
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Neurosurgery, the 2nd Hospital of Shandong University, Jinan, Shandong, China.
Jiqing
J
Zhang
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Lee-Hwa
LH
Tai
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Carolina S
CS
Ilkow
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada; Department of Medical Laboratory Technology, University of Tabuk, Tabuk, Saudi Arabia.
Almohanad A
AA
Alkayyal
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Abhirami A
AA
Ananth
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Christiano Tanese
CT
de Souza
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Jiahu
J
Wang
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Shalini
S
Sahi
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Lundi
L
Ly
Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Charles
C
Lefebvre
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Theresa J
TJ
Falls
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Kyle B
KB
Stephenson
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada; College of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia.
Ahmad B
AB
Mahmoud
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Andrew P
AP
Makrigiannis
McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
Brian D
BD
Lichty
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
John C
JC
Bell
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada; Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
David F
DF
Stojdl
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: rauer@ottawahospital.on.ca.
Rebecca C
RC
Auer
D000818:Animals; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology*; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods; D012209:Rhabdoviridae / Q000502:physiology*