Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas
Abstract Epstein-Barr virus (EBV) downregulates immune surface markers to avoid immune recognition. Pomalidomide (Pom) was previously shown to increase immune surface marker expression in EBV-infected tumor cells. We explored the mechanism by which Pom leads to these effects in EBV-infected cells. P...
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| Format: | Article |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-38156-z |
| _version_ | 1797774287449358336 |
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| author | Hannah K. Jaeger David A. Davis Ashwin Nair Prabha Shrestha Alexandra Stream Amulya Yaparla Robert Yarchoan |
| author_facet | Hannah K. Jaeger David A. Davis Ashwin Nair Prabha Shrestha Alexandra Stream Amulya Yaparla Robert Yarchoan |
| author_sort | Hannah K. Jaeger |
| collection | DOAJ |
| description | Abstract Epstein-Barr virus (EBV) downregulates immune surface markers to avoid immune recognition. Pomalidomide (Pom) was previously shown to increase immune surface marker expression in EBV-infected tumor cells. We explored the mechanism by which Pom leads to these effects in EBV-infected cells. Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1∝/β in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom’s effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas. |
| first_indexed | 2024-03-12T22:18:51Z |
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| id | doaj.art-771ce4b7f791411a9936e4e4d4d179d5 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-12T22:18:51Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-771ce4b7f791411a9936e4e4d4d179d52023-07-23T11:11:19ZengNature PortfolioScientific Reports2045-23222023-07-0113111510.1038/s41598-023-38156-zMechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomasHannah K. Jaeger0David A. Davis1Ashwin Nair2Prabha Shrestha3Alexandra Stream4Amulya Yaparla5Robert Yarchoan6HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer InstituteAbstract Epstein-Barr virus (EBV) downregulates immune surface markers to avoid immune recognition. Pomalidomide (Pom) was previously shown to increase immune surface marker expression in EBV-infected tumor cells. We explored the mechanism by which Pom leads to these effects in EBV-infected cells. Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1∝/β in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom’s effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.https://doi.org/10.1038/s41598-023-38156-z |
| spellingShingle | Hannah K. Jaeger David A. Davis Ashwin Nair Prabha Shrestha Alexandra Stream Amulya Yaparla Robert Yarchoan Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas Scientific Reports |
| title | Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas |
| title_full | Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas |
| title_fullStr | Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas |
| title_full_unstemmed | Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas |
| title_short | Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas |
| title_sort | mechanism and therapeutic implications of pomalidomide induced immune surface marker upregulation in ebv positive lymphomas |
| url | https://doi.org/10.1038/s41598-023-38156-z |
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