@article {1503172,
	title = {Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas},
	journal = {Leukemia},
	volume = {33},
	number = {1},
	year = {2019},
	month = {2019 01},
	pages = {132-147},
	abstract = {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.},
	keywords = {B7-H1 Antigen, Biomarkers, Tumor, Epstein-Barr Virus Infections, Epstein-Barr Virus Nuclear Antigens, Gene Expression Regulation, Neoplastic, Herpesvirus 4, Human, Humans, Lymphoma, Large B-Cell, Diffuse, MicroRNAs, Prognosis, T-Lymphocytes, Tumor Cells, Cultured, Viral Proteins},
	issn = {1476-5551},
	doi = {10.1038/s41375-018-0178-x},
	author = {Anastasiadou, Eleni and Stroopinsky, Dina and Alimperti, Stella and Jiao, Alan L and Pyzer, Athalia R and Cippitelli, Claudia and Pepe, Giuseppina and Severa, Martina and Rosenblatt, Jacalyn and Etna, Marilena P and Rieger, Simone and Kempkes, Bettina and Coccia, Eliana M and Sui, Shannan J Ho and Chen, Christopher S and Uccini, Stefania and Avigan, David and Faggioni, Alberto and Trivedi, Pankaj and Slack, Frank J}
}
