Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus
Background Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/6/e006388.full |
| _version_ | 1797772411026800640 |
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| author | Eric Bartee Parker Dryja Heather D Curtsinger Mee Y Bartee |
| author_facet | Eric Bartee Parker Dryja Heather D Curtsinger Mee Y Bartee |
| author_sort | Eric Bartee |
| collection | DOAJ |
| description | Background Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate. The impact of this silencing on oncolytic virotherapy (OV), however, has never been examined.Methods To address this gap in knowledge, we generated tumor cells lacking ASS1 and examined how loss of this enzyme impacted the in vivo replication and therapeutic efficacy of oncolytic myxoma virus (MYXV). We also generated a series of recombinant MYXV constructs expressing exogenous ASS1 to evaluate the therapeutic benefit of virally reconstituting Arg biosynthesis in ASS1−/− tumors.Results Our results show that the in vitro replication of oncolytic MYXV is dependent on the presence of bioavailable Arg. This dependence can be overcome by the addition of the metabolic precursor citrulline, however, this rescue requires expression of ASS1. Because of this, tumors formed from functionally ASS1−/− cells display significantly reduced MYXV replication as well as poorer therapeutic responses. Critically, both defects could be partially rescued by expressing exogenous ASS1 from recombinant oncolytic MYXVs.Conclusions These results demonstrate that intratumoral defects to Arg metabolism can serve as a novel barrier to virally induced immunotherapy and that the exogenous expression of ASS1 can improve the efficacy of OV in Arg-auxotrophic tumors. |
| first_indexed | 2024-03-12T21:51:24Z |
| format | Article |
| id | doaj.art-aa648ec51f2f46178031698f209d85d0 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:51:24Z |
| publishDate | 2023-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-aa648ec51f2f46178031698f209d85d02023-07-26T03:05:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-06-0111610.1136/jitc-2022-006388Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virusEric Bartee0Parker Dryja1Heather D Curtsinger2Mee Y Bartee3Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USAProgram in Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina, USADepartment of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USADepartment of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USABackground Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate. The impact of this silencing on oncolytic virotherapy (OV), however, has never been examined.Methods To address this gap in knowledge, we generated tumor cells lacking ASS1 and examined how loss of this enzyme impacted the in vivo replication and therapeutic efficacy of oncolytic myxoma virus (MYXV). We also generated a series of recombinant MYXV constructs expressing exogenous ASS1 to evaluate the therapeutic benefit of virally reconstituting Arg biosynthesis in ASS1−/− tumors.Results Our results show that the in vitro replication of oncolytic MYXV is dependent on the presence of bioavailable Arg. This dependence can be overcome by the addition of the metabolic precursor citrulline, however, this rescue requires expression of ASS1. Because of this, tumors formed from functionally ASS1−/− cells display significantly reduced MYXV replication as well as poorer therapeutic responses. Critically, both defects could be partially rescued by expressing exogenous ASS1 from recombinant oncolytic MYXVs.Conclusions These results demonstrate that intratumoral defects to Arg metabolism can serve as a novel barrier to virally induced immunotherapy and that the exogenous expression of ASS1 can improve the efficacy of OV in Arg-auxotrophic tumors.https://jitc.bmj.com/content/11/6/e006388.full |
| spellingShingle | Eric Bartee Parker Dryja Heather D Curtsinger Mee Y Bartee Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus Journal for ImmunoTherapy of Cancer |
| title | Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus |
| title_full | Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus |
| title_fullStr | Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus |
| title_full_unstemmed | Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus |
| title_short | Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus |
| title_sort | defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus |
| url | https://jitc.bmj.com/content/11/6/e006388.full |
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