Jiang Ying, Cai Gangli, Lin Jun, Zhang Jing, Bo Zhilei, Li Ying, Wang Chun, Tong Yin
1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080 People's Republic of China.
Department of Hematology, JinHua Hospital of TCM, 439 Shuangxi West Road, Jinhua, 321017 People's Republic of China.
Infect Agent Cancer. 2019 Aug 8;14:20. doi: 10.1186/s13027-019-0234-9. eCollection 2019.
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 (EBVDLBCL) has not been addressed although it has been suggested that B7-H4 could promote tumor growth and metastatic progression in certain cancers.
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.
EBVDLBCL 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.
Our study reveals a critical role of B7-H4 in EBVDLBCL development by regulating cell survival and apoptosis through the Erk and Akt signalling pathways. Targetting B7-H4 may be promising in the therapy of EBVDLBCL.
B7-H4是B7家族成员之一，可能作为一个新的可靶向免疫检查点分子。据报道，血清B7-H4水平升高可能与淋巴瘤相关。然而，尽管有研究提示B7-H4在某些癌症中可促进肿瘤生长和转移进展，但B7-H4在爱泼斯坦-巴尔病毒阳性弥漫性大B细胞淋巴瘤（EBV-DLBCL）中的作用尚未得到阐明。
2005年1月至2017年11月期间，上海交通大学医学院附属上海第一人民医院血液科对260例弥漫性大B细胞淋巴瘤（DLBCL）样本进行原位杂交检测EBV编码的小RNA（EBV-EBER）。采用免疫组织化学法评估DLBCL肿瘤组织中B7-H4的表达水平。此外，在DLBCL细胞系中进一步研究B7-H4在DLBCL中的作用。
在我们的研究中，EBV-DLBCL患者的总生存期（OS）和无进展生存期（PFS）明显较低。我们发现，在260例DLBCL患者中，有16例EBV亚组病例中B7-H4显著过表达。我们进一步发现，淋巴母细胞中的EBV感染导致B7-H4表达增强，随后细胞活力增加，凋亡减少。相反，抑制B7-H4同时损害细胞活力并诱导凋亡。机制上，抑制B7-H4导致磷酸化的Erk 1/2和Akt减少。
我们的研究揭示了B7-H4在EBV-DLBCL发生发展中通过Erk和Akt信号通路调节细胞存活和凋亡的关键作用。靶向B7-H4可能是治疗EBV-DLBCL的一个有前景的方法。
