%0 Journal Article %J Leukemia %D 2018 %T Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas %A Anastasiadou, Eleni %A Stroopinsky, Dina %A Alimperti, Stella %A Jiao, Alan L %A Pyzer, Athalia R %A Cippitelli, Claudia %A Pepe, Giuseppina %A Severa, Martina %A Rosenblatt, Jacalyn %A Etna, Marilena P %A Rieger, Simone %A Kempkes, Bettina %A Coccia, Eliana M %A Sui, Shannan J Ho %A Chen, Christopher S %A Uccini, Stefania %A Avigan, David %A Faggioni, Alberto %A Trivedi, Pankaj %A Slack, Frank J %X 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 oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. 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. %B Leukemia %8 2018 Jun 26 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/29946193?dopt=Abstract %R 10.1038/s41375-018-0178-x