Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas
- PMID: 29946193
- PMCID: PMC6327052
- DOI: 10.1038/s41375-018-0178-x
Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas
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.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Figures
![Fig. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig1_HTML.gif)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig2_HTML.gif)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig3_HTML.gif)
![Fig. 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig4_HTML.gif)
![Fig. 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig5_HTML.gif)
![Fig. 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig6_HTML.gif)
![Fig. 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6327052/bin/41375_2018_178_Fig7_HTML.gif)
Similar articles
-
Targeting latent viral infection in EBV-associated lymphomas.Front Immunol. 2024 Feb 23;15:1342455. doi: 10.3389/fimmu.2024.1342455. eCollection 2024. Front Immunol. 2024. PMID: 38464537 Free PMC article. Review.
-
Epstein-Barr virus-encoded EBNA2 downregulates ICOSL by inducing miR-24 in B-cell lymphoma.Blood. 2024 Feb 1;143(5):429-443. doi: 10.1182/blood.2023021346. Blood. 2024. PMID: 37847858 Free PMC article.
-
EBNA2-deleted Epstein-Barr virus (EBV) isolate, P3HR1, causes Hodgkin-like lymphomas and diffuse large B cell lymphomas with type II and Wp-restricted latency types in humanized mice.PLoS Pathog. 2020 Jun 15;16(6):e1008590. doi: 10.1371/journal.ppat.1008590. eCollection 2020 Jun. PLoS Pathog. 2020. PMID: 32542010 Free PMC article.
-
EBV microRNA-BHRF1-2-5p targets the 3'UTR of immune checkpoint ligands PD-L1 and PD-L2.Blood. 2019 Dec 19;134(25):2261-2270. doi: 10.1182/blood.2019000889. Blood. 2019. PMID: 31856276 Free PMC article.
-
Prognostic and clinicopathological significance of PD-1/PD-L1 expression in the tumor microenvironment and neoplastic cells for lymphoma.Int Immunopharmacol. 2019 Dec;77:105999. doi: 10.1016/j.intimp.2019.105999. Epub 2019 Nov 6. Int Immunopharmacol. 2019. PMID: 31704289 Review.
Cited by
-
The Possible Role of Pathogens and Chronic Immune Stimulation in the Development of Diffuse Large B-Cell Lymphoma.Biomedicines. 2024 Mar 14;12(3):648. doi: 10.3390/biomedicines12030648. Biomedicines. 2024. PMID: 38540261 Free PMC article. Review.
-
Carcinogenic mechanisms of virus-associated lymphoma.Front Immunol. 2024 Feb 28;15:1361009. doi: 10.3389/fimmu.2024.1361009. eCollection 2024. Front Immunol. 2024. PMID: 38482011 Free PMC article. Review.
-
Presence of Epstein-Barr virus (EBV) antigens detected by sensitive methods has no influence on local immune environment in diffuse large B cell lymphoma.Cancer Immunol Immunother. 2024 Jan 27;73(2):29. doi: 10.1007/s00262-023-03617-x. Cancer Immunol Immunother. 2024. PMID: 38280007 Free PMC article.
-
Expression of the immune checkpoint molecules PD‑L1 and PD‑1 in EBV‑associated lymphoproliferative disorders: A meta‑analysis.Exp Ther Med. 2023 Nov 10;27(1):7. doi: 10.3892/etm.2023.12294. eCollection 2024 Jan. Exp Ther Med. 2023. PMID: 38223325 Free PMC article.
-
Mechanisms of T cell evasion by Epstein-Barr virus and implications for tumor survival.Front Immunol. 2023 Dec 21;14:1289313. doi: 10.3389/fimmu.2023.1289313. eCollection 2023. Front Immunol. 2023. PMID: 38179040 Free PMC article. Review.
References
-
- Kuze T, Nakamura N, Hashimoto Y, Sasaki Y, Abe M. The characteristics of Epstein−Barr virus (EBV)-positive diffuse large B-cell lymphoma: comparison between EBV(+) and EBV(−) cases in Japanese population. Jpn J Cancer Res: Gann. 2000;91:1233–40. doi: 10.1111/j.1349-7006.2000.tb00909.x. - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials