EBI3通过调节Th17，PD-L1在肿瘤微环境中发挥免疫抑制作用的机制研究

Epstein-Barr virus-Induced gene 3(EBI3) protein is highly expressed in placental cells in pregnancy and has roles in maintenance of immune tolerance of the human maternal body toward the fetus. Morevoer,EBI3 has been found to highly expressed in several tumor tissue. However, the significance of EBI3 in carcinogenesis and tumor development was not clarified. Our pilot studies showed that the growth of tumor can be heavily suppressed in EBI3-/- mice. It is tempting to speculate that expression of EBI3 may promote tumor growth. EBI3, a secretory glycoprotein, has been shown to form IL-27,IL-35 and homodimer. It has been reported that EBI3 has strong immunosuppressive function in autoimmune disease and infection via inhibiting the function and differentiation of Th17 cells and adjusting the PD-L1 signal. In view of this, we speculate that EBI3 has strong immunosuppressive function in the tumor micro-environment by inhibiting Th17 cells and promoting the PD-L1 expression. We have confirmed Th17 changes in our pilot studies. Our proposed research aims at identifying the immunosuppressive function and how EBI3 can create strong immunosuppressive via Th17 and PD-L1 pathway. Specifically, we will validate our speculation in human colorectal tumor tissue. 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.

EB病毒诱导蛋白（EBI3）在妊娠期间胎盘高表达，与免疫抑制密切相关。研究发现，EBI3表达于多种肿瘤，但在肿瘤发生发展中的作用尚不明确。我们前期在EBI3敲除小鼠中接种肿瘤，发现肿瘤生长较野生型明显延缓，反面提示EBI3表达可能促进肿瘤生长，但机制不清。EBI3作为一种分泌性糖蛋白，可以参与形成IL-27、IL-35或形成同源二聚体，在抑制Th17细胞功能和调节PD-L1信号中发挥对自身免疫和炎症的抑制作用。因此，我们推测：EBI3可能在肿瘤微环境中通过抑制Th17细胞，促进PD-L1表达发挥免疫抑制作用，进而促进免疫逃逸，促肿瘤生长。我们在前期研究中初步证实了Th17的变化，在本项目中，我们拟进一步证实EBI3的免疫抑制作用，阐明其免疫调节机制，并进一步在人肿瘤组织中进行验证。本项目的实施，不仅仅有助于理解EBI3介导肿瘤免疫逃逸的机制，还将为靶向抑制EBI3治疗肿瘤提供研究基础。