Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Indeed, Epstein-Barr virus (EBV) positive Hodgkin’s lymphoma and gastric adenocarcinomas have higher Programmed Cell Death Ligand, PD-L1, expression. However, how EBV alters ICs in the context of its preferred host, the B lymphocyte and lymphomas, is unknown. Here, we used Burkitt lymphoma (BL), diffuse large B cell lymphomas (DLBCL) and their EBV infected or EBNA2 transfected derivatives to address this question. EBV latency III cells expressed high levels of PD-L1. In a DLBCL model, we found that EBNA2 but not LMP1 is sufficient to induce PD-L1. The upregulation of PD-L1 was confirmed in estrogen inducible EBNA2 carrying B lymphoma cells. Clinical samples from DLBCL patients showed that EBV infected, latency III cases expressed high levels of PD-L1. The PD-L1 targeting oncosuppressor miR-34a was downregulated in EBNA2 transfected cells. miR-34a reconstitution in EBNA2 expressing DLBCL reduced PD-L1 expression and increased their immunogenicity in 2D mixed lymphocyte reactions (MLR) and 3D microfluidic chip based MLRs. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for diagnosis and combinatorial immunotherapy approaches which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.
Citation Format: Anastasiadou Eleni, Stroopinsky Dina, Stella Alimperti, Alan Jiao, Athalia Pyzer, Claudia Cipitelli, Martina Severa, Christopher S. Chen, Stefania Uccini, David Avigan, Alberto Faggioni, Pankaj Trivedi, Frank J. Slack. Epstein-Barr virus encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B cell lymphomas [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A16.