• EBNA2 reduces ICOSL expression in B cell lymphoma such as DLBCL through miR-24.

  • Silencing of miR-24 reconstitutes tumor immunogenicity and induces apoptosis in diffuse large B cell lymphoma.

Hematological malignancies like Burkitt lymphoma (BL), Hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) cause significant morbidity in humans. A substantial number of these lymphomas, particularly, HL and DLBCLs have poorer prognosis due to their association with Epstein-Barr virus (EBV). Our earlier studies have shown that EBV encoded nuclear antigen EBNA2 upregulates PD-L1 in DLBCL and BLs by downregulating miR-34a. Here, we investigated whether EBNA2 affects the inducible co-stimulator ligand, ICOSL, a molecule required for efficient recognition of tumor cells by T cells through the engagement of ICOS on the latter. In virus-infected and EBNA2-transfected B-lymphoma cells, ICOSL expression was reduced. Our investigation of the molecular mechanisms revealed that this was due to an increase in miR-24 by EBNA2. By using ICOSL 3'UTR-Luc reporter system, we validated that ICOSL is an authentic miR-24 target. Transfection of anti-miR-24 molecules in EBNA2 expressing lymphoma cells reconstituted ICOSL expression and increased tumor immunogenicity in mixed lymphocyte reactions. Since miR-24 is known to target c-MYC, an oncoprotein positively regulated by EBNA2, we analyzed its expression in anti-miR-24 transfected lymphoma cells. Indeed, the reduction of miR-24 in EBNA2 expressing DLBCL further elevated c-MYC and increased apoptosis. Consistent with the in vitro data, EBNA2 positive DLBCL biopsies expressed low ICOSL and high miR-24. We suggest that EBV evades host immune responses through EBNA2 by inducing miR-24 to reduce ICOSL expression and for simultaneous rheostatic maintenance of pro-proliferative c-MYC levels. Overall, these data identify miR-24 as potential therapeutically relevant target in EBV associated lymphomas.

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