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

Abstract 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.