B7-H4 is highly expressed in aggressive Epstein-Barr virus positive diffuse large B-cell lymphoma and inhibits apoptosis through upregulating Erk1/2 and Akt signalling pathways

BACKGROUND: B7-H4 is among the B7 family members which may serve as a new targetable immune checkpoint molecule. It was reported that high level of serum B7-H4 level may be correlated with lymphoma. Nevertheless, the role of B7-H4 in Epstein-Barr Virus-Positive diffuse large B cell lymphoma (EBV(+)DLBCL) has not been addressed although it has been suggested that B7-H4 could promote tumor growth and metastatic progression in certain cancers. METHODS: Between January 2005 and November 2017 at the department of Hematology, Shanghai Jiao Tong University School of Medicine affiliated Shanghai General Hospital 260 DLBCL samples were analyzed for EBV-encoded small RNA (EBV-EBER) by in situ hybridization. The expression level of B7-H4 in DLBCL tumor tissue was evaluated by immunohistochemistry. Furthermore, the role of B7-H4 in DLBCL was further investigated in DLBCL cell line. RESULTS: EBV(+)DLBCL patients suffered from markedly lower overall survival (OS) and progression-free survival (PFS) rates in our study. We showed that B7-H4 was significantly overexpressed in 16 EBV(+)-subgroup cases out of 260 DLBCL patients. We further found that EBV infection in lymphoblast cells led to enhanced expression of B7-H4 followed by increased cell viability and reduced apoptosis. In contrast, inhibition of B7-H4 simultaneously impaired cell viability and induced apoptosis. Mechanistically, inhibiting B7-H4 resulted in decreased phosphorylation Erk 1/2 and Akt. CONCLUSION: Our study reveals a critical role of B7-H4 in EBV(+)DLBCL development by regulating cell survival and apoptosis through the Erk and Akt signalling pathways. Targetting B7-H4 may be promising in the therapy of EBV(+)DLBCL.