B7-H1分子表达调控弥漫大B细胞淋巴瘤微环境诱导免疫逃逸的机制研究

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin's lymphoma. Despite of the improvement in its clinical efficacy recent years, there are still lots of patients died of recurrence or refractory. The B7 family molecules play an important role in regulating T cell immune antigen. Until now, it has been found that B7-H1 molecules, an important member of B7 family molecules, play a vital role in the occurrence and development of certain tumors, which have not been reported in DLBCL. It has been found in the preliminary study of the project that DLBCL cells are able to express B7-H1 molecule, which can be remarkably upregulated through stimulating the TLR4 receptor. Combining with the research of immune escape mediated by B7-H1 molecules, we speculate that DLBCL cells may also escape from autoimmune attack by expression of B7-H1 molecule which regulate the tumor microenvironment.Consequently, on the basis of previous research, our project is intended to adopt human primary DLBCL tumor cell and DLBCL cell line as the research object, clarify the specific immune escape mechanism of DLBCL cells mediated by B7-H1 molecule, and explain the specific regulatory mechanism of up regulating of B7-H1 molecule after activating of TLRs receptor on DLBCL cells through the method of immunology and molecular biology. The research results will provide experimental evidence for designing new DLBCL biotherapeutics.

弥漫大B细胞淋巴瘤（DLBCL）是最常见的一种侵袭性非霍奇金淋巴瘤。尽管近来其临床疗效有所改善，但仍有大部分患者死于复发或难治。B7家族分子是调节T细胞免疫的重要抗原，目前已发现其重要成员B7-H1分子在某些肿瘤发生发展中起重要作用，但在DLBCL中的研究尚未报道。本项目组前期研究发现DLBCL细胞能表达B7-H1分子，且通过刺激TLR4受体使B7-H1分子表达明显上调。结合B7-H1介导肿瘤免疫逃逸的研究，本项目推测DLBCL细胞可能通过表达B7-H1分子调控肿瘤微环境逃避自身免疫攻击。故本课题拟以人原代DLBCL肿瘤细胞及DLBCL细胞系为研究对象，在已有的研究基础上，采用免疫学和分子生物学研究方法，阐明B7-H1分子介导DLBCL免疫逃逸的具体作用机制，解析DLBCL细胞TLRs受体刺激活化后上调B7-H1分子的具体调控机制。研究成果将为研发新的DLBCL生物治疗靶向提供实验依据。

弥漫大B细胞淋巴瘤（DLBCL）是最常见的一种侵袭性非霍奇金淋巴瘤。尽管近来其临床疗效有所改善，但仍有大部分患者死于复发或难治。B7家族分子是调节T细胞免疫的重要抗原，目前已发现其重要成员B7-H1分子在某些肿瘤发生发展中起重要作用，但在DLBCL中的研究尚未报道。本项目主要研究结果，1）本项目检测了对50例新发DLBCL患者的B7-H1的表达水平，发现non-GCB亚型的DLBCL表达水平高于GCB亚型，且与不良预后和较低的总生存率（OS）有关。2）体外细胞系研究也发现，ABC亚型的DLBCL细胞系有较高的B7-H1表达水平。3）针对低B7-H1表达细胞系，采用细胞因子选择性诱导（如IFNγ,TNFα等细胞因子）该细胞系，发现研究B7-H1表达有轻度增高。4）初步研究发现敲除或增加B7-H1表达后，DLBCL小鼠肿瘤能够减慢生长。本项目采用免疫学和分子生物学等研究方法，通过研究DLBCL患者以及肿瘤细胞系的B7-H1的表达，部分阐明B7家族分子介导的免疫调控在DLBCL免疫逃逸机制中的具体作用，并为B7-H1阻断以及激活T细胞介导免疫效应的疗法提供了实验依据。可为复发难治的DLBCL进一步设计新的生物治疗策略提供新的思路。