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Anastasiadou, E.* ; Stroopinsky, D.* ; Alimperti, S.* ; Jiao, A.L.* ; Pyzer, A.R.* ; Cippitelli, C.* ; Pepe, G.* ; Severa, M.* ; Rosenblatt, J.* ; Etna, M.P.* ; Rieger, S. ; Kempkes, B. ; Coccia, E.M.* ; Sui, S.J.H.* ; Chen, C.S.* ; Uccini, S.* ; Avigan, D.* ; Faggioni, A.* ; Trivedi, P.* ; Slack, F.J.*

Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas.

Leukemia 33, 132–147 (2018)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein-Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting on-cosuppressor microRNA miR-34a was down-regulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-Ll. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Classical Hodgkin Lymphoma; Death Ligand 1; C-myc; Differential Regulation; Nuclear Antigen-2; Gene-expression; Infection; Cancer; Model; Transformation
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 33, Issue: 1, Pages: 132–147 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)