Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas

• Published in: Scientific reports Vol. 13; no. 1; pp. 11596 - 15
• Main Authors: Jaeger, Hannah K., Davis, David A., Nair, Ashwin, Shrestha, Prabha, Stream, Alexandra, Yaparla, Amulya, Yarchoan, Robert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67; 631/67/1059; 631/67/1858; AKT protein; CD86 antigen; Cytokines; Epstein-Barr virus; Gene expression; Humanities and Social Sciences; Ikaros protein; Inflammation; IP-10 protein; Kinases; Lymphoma; mRNA; multidisciplinary; Phosphorylation; PU.1 protein; Science; Science (multidisciplinary); Surface markers; Tumor cells; Up-regulation
• DOI: 10.1038/s41598-023-38156-z
• ISSN: 2045-2322

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.