EBI3通过PD-1/PD-L1通路调控Treg 细胞表达介导DLBCL肿瘤免疫抑制机制的研究

Epstein-Barr virus-induced gene 3 (EBI3), expressed throughout pregnancy, suggests that EBI3 plays an important role in immunosuppression in the fetal-maternal relationship. Moreover, EBI3 was found to be highly expressed in DLBCL, associated with poor prognosis. However, the significance of EBI3 in carcinogenesis and tumor development was not clarified. EBI3, as a downstream signal of FOXP3, can promote T regulatory cells (Tregs) proliferation and inhibit the function of effector T cells. Our pilot studies showed the relevance of Tregs and of EBI3 in controlling the growth of tumor. Recent studies suggest that Tregs constitutively express PD-1, which was involved in the development and function of Treg cells. Thus, we supposed that EBI3 is required for immune suppressive function by regulating PD-1/PD-L1 pathway and promoting the proliferation of Treg cells in DLBCL. In our research, we aimed at identifying the immunosuppressive function and how EBI3 can create strong immunosuppressive via PD-1/PD-L1 pathway and Tregs using DLBCL mice-model. And we will validate our speculation in human DLBCL tumor tissue and blood samples. We strongly believe that our proposed research on identifying EBI3’s immunosuppressive function will establish the fundation to choose EBI3 as an anti-tumor immune therapeutic target and prognostic indicator.

EB病毒诱导蛋白（EBI3）在孕期高表达，与免疫抑制密切相关。研究发现，EBI3在DLBCL中高表达，提示预后不良，但EBI3调控DLBCL发生发展中的机制尚不明确。EBI3作为调节性T细胞Foxp3转录因子下游靶位，促进调节性T细胞（Treg）的增殖，抑制效应性T细胞功能。我们前期研究证实，EBI3促进Treg增殖，促肿瘤生长。此外，PD-1在Treg细胞上持续表达，调节PD-L1通路影响Treg细胞的分化和功能。因此，我们推测：EBI3可通过PD-1/PD-L1信号通路，促进Treg细胞增殖，发挥免疫抑制作用，促肿瘤生长。因此，我们拟建立小鼠DLBCL肿瘤模型，进一步证实EBI3的免疫抑制作用，阐明其免疫调节机制，并在人肿瘤组织及血液标本中进行验证。本项目的实施，不仅有助于理解EBI3介导肿瘤免疫逃逸的机制，还为EBI3作为DLBCL预后指标及治疗靶点奠定理论基础。

弥漫大B细胞淋巴瘤是常见的血液肿瘤之一，目前治愈率可达40-60%，仍有高达40%的复发难治患者，新的预后指标及治疗靶点的探讨是临床亟待解决的问题。本课题性旨在探讨EBI3对DLBCL的治疗靶点及预后指标的可行性，以及其作用机制，为DLBCL治疗提供新的思路。研究结果表明，EBI3在高危弥漫大B细胞患者中表达，其表达与患者预后相关，高表达患者预后不良，1y-EFS下降。同时我们通过慢病毒sh-RNA-EBI3，建立稳定高表达和低表达的细胞株，通过研究发现，下调EBI3的表达，可明显抑制细胞的生长及转移，延长荷瘤小鼠的生存。同时，研究发现，EBI3可调控肿瘤微环境，下调EBI3的表达，可抑制肿瘤血管生成，促进细胞的凋亡，同时改善肿瘤免疫微环境，提高CTL杀伤活性，下调Th17和Treg细胞的表达，有益于发挥肿瘤免疫控制肿瘤的进展。因此，EBI3可作为一个预后指标和治疗的潜在靶点，下调EBI3的表达有利于增强抗肿瘤免疫而抑制肿瘤发生发展。