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.
Highlights
These authors contributed : Frank J Slack and Pankaj Trivedi.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Among non-Hodgkin lymphoma (NHL), more than 95% of endemic Burkitt lymphoma (BL) are associated with Epstein−Barr virus (EBV)
PD-L1 expression is induced in latency III-expressing BLs, in vitro infected BLs and diffuse large B-cell lymphomas (DLBCL) and EBNA2transfected cells
Two additional BL cell lines, Jijoye, which is positive for EBNA2 expression expressed PD-L1, while EBNA2-deleted Daudi BL lacked PD-L1 expression (Fig. 1a)
Summary
These authors contributed : Frank J Slack and Pankaj Trivedi. Among non-Hodgkin lymphoma (NHL), more than 95% of endemic BLs are associated with Epstein−Barr virus (EBV). It is noteworthy that the annual global number of cases of EBV-positive DLBCLs supersede the total number of BLs. EBV is the cause of lymphomas arising in immunocompromised individuals such as AIDS and transplant patients [3]. EBV is the cause of lymphomas arising in immunocompromised individuals such as AIDS and transplant patients [3] This clearly suggests that EBV’s ability to cause cancer lies in its capacity to evade host immune surveillance
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