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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)
Verlagsversion Forschungsdaten 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Leukemia
Quellenangaben Band: 33, Heft: 1, Seiten: 132–147 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Macmillan Building, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)