STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation
Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive soft-tissue sarcoma amenable only to surgical resection. Oncolytic herpes simplex viruses (oHSVs) are a promising experimental therapy. We previously showed that basal interferon (IFN) and nuclear factor κB (NFκB) signaling upregula...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Molecular Therapy: Oncolytics |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S237277051930083X |
| _version_ | 1818137207904403456 |
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| author | Joel M. Lee Mohammed G. Ghonime Kevin A. Cassady |
| author_facet | Joel M. Lee Mohammed G. Ghonime Kevin A. Cassady |
| author_sort | Joel M. Lee |
| collection | DOAJ |
| description | Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive soft-tissue sarcoma amenable only to surgical resection. Oncolytic herpes simplex viruses (oHSVs) are a promising experimental therapy. We previously showed that basal interferon (IFN) and nuclear factor κB (NFκB) signaling upregulate IFN-stimulated gene (ISG) expression and restrict efficient viral infection and cell-to-cell spread in ∼50% of tested MPNSTs. Stimulator of Interferon Genes (STING) integrates DNA sensor activity and mediates downstream IFN signaling in infected cells. We sought to identify STING’s role in oHSV resistance and contribution to basal ISG upregulation in MPNSTs. We show that the level of STING activity in human MPNST cell lines is predictive of oHSV sensitivity and that resistant cell lines have intact mechanisms for detection of cytosolic double-stranded DNA (dsDNA). Furthermore, we show that STING downregulation renders MPNSTs more permissive to oHSV infection and cell-to-cell spread. While next-generation viruses can exploit this loss of STING activity, first-generation viruses remain restricted. Finally, STING is not integral to the previously-observed basal ISG upregulation, indicating that other pathways contribute to basal IFN signaling in resistant MPNSTs. These data broaden our understanding of the intrinsic pathways in MPNSTs and their role in oHSV resistance and offer potential targets to potentiate oncolytic virus activity. Keywords: STING, MPNST, ISG, oHSV, oncolytic virus, pattern recognition receptor, sarcoma, cGAS, Neurofibromatosis |
| first_indexed | 2024-12-11T09:52:38Z |
| format | Article |
| id | doaj.art-8fdfe0bdf8b94e3b9310378ec2e79f38 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-11T09:52:38Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-8fdfe0bdf8b94e3b9310378ec2e79f382022-12-22T01:12:22ZengElsevierMolecular Therapy: Oncolytics2372-77052019-12-011591100STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene UpregulationJoel M. Lee0Mohammed G. Ghonime1Kevin A. Cassady2The Ohio State University College of Medicine, Biomedical Sciences Graduate Program, Columbus, OH 43210, USAAbigail Wexner Research Institute at Nationwide Children’s Hospital Center for Childhood Cancer and Blood Disorders, Columbus, OH 43205, USA; The Ohio State University, Columbus, OH 43210, USAAbigail Wexner Research Institute at Nationwide Children’s Hospital Center for Childhood Cancer and Blood Disorders, Columbus, OH 43205, USA; The Ohio State University, Columbus, OH 43210, USA; Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA; Corresponding author: Kevin A. Cassady, Abigail Wexner Research Institute at Nationwide Children’s Hospital Center for Childhood Cancer and Blood Diseases, 700 Children’s Drive, Columbus, OH 43205, USA.Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive soft-tissue sarcoma amenable only to surgical resection. Oncolytic herpes simplex viruses (oHSVs) are a promising experimental therapy. We previously showed that basal interferon (IFN) and nuclear factor κB (NFκB) signaling upregulate IFN-stimulated gene (ISG) expression and restrict efficient viral infection and cell-to-cell spread in ∼50% of tested MPNSTs. Stimulator of Interferon Genes (STING) integrates DNA sensor activity and mediates downstream IFN signaling in infected cells. We sought to identify STING’s role in oHSV resistance and contribution to basal ISG upregulation in MPNSTs. We show that the level of STING activity in human MPNST cell lines is predictive of oHSV sensitivity and that resistant cell lines have intact mechanisms for detection of cytosolic double-stranded DNA (dsDNA). Furthermore, we show that STING downregulation renders MPNSTs more permissive to oHSV infection and cell-to-cell spread. While next-generation viruses can exploit this loss of STING activity, first-generation viruses remain restricted. Finally, STING is not integral to the previously-observed basal ISG upregulation, indicating that other pathways contribute to basal IFN signaling in resistant MPNSTs. These data broaden our understanding of the intrinsic pathways in MPNSTs and their role in oHSV resistance and offer potential targets to potentiate oncolytic virus activity. Keywords: STING, MPNST, ISG, oHSV, oncolytic virus, pattern recognition receptor, sarcoma, cGAS, Neurofibromatosishttp://www.sciencedirect.com/science/article/pii/S237277051930083X |
| spellingShingle | Joel M. Lee Mohammed G. Ghonime Kevin A. Cassady STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation Molecular Therapy: Oncolytics |
| title | STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation |
| title_full | STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation |
| title_fullStr | STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation |
| title_full_unstemmed | STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation |
| title_short | STING Restricts oHSV Replication and Spread in Resistant MPNSTs but Is Dispensable for Basal IFN-Stimulated Gene Upregulation |
| title_sort | sting restricts ohsv replication and spread in resistant mpnsts but is dispensable for basal ifn stimulated gene upregulation |
| url | http://www.sciencedirect.com/science/article/pii/S237277051930083X |
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