Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer.

Autor:	van Vloten JP; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Matuszewska K; Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada., Minow MAA; Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada., Minott JA; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Santry LA; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Pereira M; Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada., Stegelmeier AA; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., McAusland TM; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Klafuric EM; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Karimi K; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Colasanti J; Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada., McFadden DG; Biodesign Institute, Arizona State University, Tempe, Arizona, USA., Petrik JJ; Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada., Bridle BW; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada., Wootton SK; Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada kwootton@uoguelph.ca.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Mar; Vol. 10 (3).
DOI:	10.1136/jitc-2021-004335
Abstrakt:	Background: Novel therapies are needed to improve outcomes for women diagnosed with ovarian cancer. Oncolytic viruses are multifunctional immunotherapeutic biologics that preferentially infect cancer cells and stimulate inflammation with the potential to generate antitumor immunity. Herein we describe Parapoxvirus ovis (Orf virus (OrfV)), an oncolytic poxvirus, as a viral immunotherapy for ovarian cancer. Methods: The immunotherapeutic potential of OrfV was tested in the ID8 orthotopic mouse model of end-stage epithelial ovarian carcinoma. Immune cell profiling, impact on secondary lesion development and survival were evaluated in OrfV-treated mice as well as in Batf3 knockout, mice depleted of specific immune cell subsets and in mice where the primary tumor was removed. Finally, we interrogated gene expression datasets from primary human ovarian tumors from the International Cancer Genome Consortium database to determine whether the interplay we observed between natural killer (NK) cells, classical type 1 dendritic cells (cDC1s) and T cells exists and influences outcomes in human ovarian cancer. Results: OrfV was an effective monotherapy in a murine model of advanced-stage epithelial ovarian cancer. OrfV intervention relied on NK cells, which when depleted abrogated antitumor CD8 + T-cell responses. OrfV therapy was shown to require cDC1s in experiments with BATF3 knockout mice, which do not have mature cDC1s. Furthermore, cDC1s governed antitumor NK and T-cell responses to mediate antitumor efficacy following OrfV. Primary tumor removal, a common treatment option in human patients, was effectively combined with OrfV for optimal therapeutic outcome. Analysis of human RNA sequencing datasets revealed that cDC1s correlate with NK cells in human ovarian cancer and that intratumoral NK cells correlate positively with survival. Conclusions: The data herein support the translational potential of OrfV as an NK stimulating immunotherapeutic for the treatment of advanced-stage ovarian cancer. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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