EBV microRNA-BHRF1-2-5p targets the 3′UTR of immune checkpoint ligands PD-L1 and PD-L2
Autor: | Gayathri Thillaiyampalam, Sally Mujaj, Cameron Snell, Frank Vari, Maher K. Gandhi, Madeline Gough, Jamie P. Nourse, Colm Keane, Soi Cheng Law, Muhammed B. Sabdia, Rachael A. West, Alexandre S. Cristino, Jay Gunawardana |
---|---|
Rok vydání: | 2019 |
Předmět: |
Untranslated region
Epstein-Barr Virus Infections Herpesvirus 4 Human Cell cycle checkpoint Immunobiology and Immunotherapy Immunology Biology Biochemistry B7-H1 Antigen hemic and lymphatic diseases PD-L1 microRNA Gene expression Humans Three prime untranslated region Germinal center Cell Biology Hematology Programmed Cell Death 1 Ligand 2 Protein Immune checkpoint Neoplasm Proteins MicroRNAs biology.protein Cancer research RNA Viral Lymphoma Large B-Cell Diffuse |
Zdroj: | Blood. 134:2261-2270 |
ISSN: | 1528-0020 0006-4971 |
Popis: | Epstein-Barr virus–positive (EBV(+)) diffuse large B-cell lymphomas (DLBCLs) express high levels of programmed death ligand 1 (PD-L1) and PD-L2. MicroRNA (miR) regulation is an important mechanism for the fine-tuning of gene expression via 3′-untranslated region (3′UTR) targeting, and we have previously demonstrated strong EBV miR expression in EBV(+) DLBCL. Whereas the EBV latent membrane protein-1 (LMP1) is known to induce PD-L1/L2, a potential counterregulatory role of EBV miR in the fine-tuning of PD-L1/L2 expression remains to be established. To examine this, a novel in vitro model of EBV(+) DLBCL was developed, using the viral strain EBV WIL, which unlike common laboratory strains retains intact noncoding regions where several EBV miRs reside. This enabled interrogation of the relationship among EBV latency genes, cell of origin (COO), PD-L1, PD-L2, and EBV miRs. The model successfully recapitulated the full spectrum of B-cell differentiation, with 4 discrete COO phases: early and late germinal center B cells (GCBs) and early and late activated B cells (ABCs). Interestingly, PD-L1/L2 levels increased markedly during transition from late GCB to early ABC phase, after LMP1 upregulation. EBV miR–BamHI fragment H rightward open reading frame 1 (BHRF1)–2-5p clustered apart from other EBV miRs, rising during late GCB phase. Bioinformatic prediction, together with functional validation, confirmed EBV miR-BHRF1-2-5p bound to PD-L1 and PD-L2 3′UTRs to reduce PD-L1/L2 surface protein expression. Results indicate a novel mechanism by which EBV miR-BHRF1-2-5p plays a context-dependent counterregulatory role to fine-tune the expression of the LMP1-driven amplification of these inhibitory checkpoint ligands. Further identification of immune checkpoint–targeting miRs may enable potential novel RNA-based therapies to emerge. |
Databáze: | OpenAIRE |
Externí odkaz: |