雌激素调控PD-1/PD-L1信号通路对子宫内膜异位症细胞免疫的调节作用及机制

Endometriosis is an estrogen-dependent disease related to impaired immunoregulation. Recent researches have revealed that PD-1 and its ligand PD-L1 are primarily expressed on different kinds of immune cells, while PD-L1 is also expressed on a wide variety of nonhematopoietic tissues or cells, even tumor cells, indicating their significant roles in cellular immunity as well as cancer immune escape. Other studies suggest that intracellular signals of PD-1 are transduced through PI3K/AKT pathway and estradiol plays an important role in immunosuppression by upregulating the expression of PD-1 on T lymphocytes. But there is still no report on whether this signaling pathway is expressed abnormally in endometriosis. Our previous studies have found that PD-1 is overexpressed in endometriosis, at the same time estradiol could promote endometriosis through various mechanisms with upregulation of PI3K/AKT pathway. Based on these, we propose a hypothesis that PD-1/PD-L1 signaling pathway is up regulated by estradiol, which suppresses functions of T lymphocytes, then allows ectopic implantation of endometrium to survive resulting in endometriosis. The project is going to have a look on the impact of this pathway in endometriosis through three different levels including in vitro, in vivo and with pathological specimens and explore the influence of estradiol on it and its exact intracellular signal transductions. This project is aimed at clarifying the pathogenesis of endometriosis, and making theoretical explanation on the anti-estrogen therapy and PD-1/PD-L1 pathway target therapy against endometriosis.

子宫内膜异位症是一种免疫调节异常的雌激素依赖性疾病。近期研究发现，PD-1及其配体PD-L1表达于多种免疫细胞，在组织和肿瘤细胞中也有表达，在细胞免疫和肿瘤的免疫逃逸中发挥重要作用。但该通路在内异症中是否异常表达并发挥免疫抑制作用尚未见报道。研究提示PD-1分子的细胞内信号由PI3K/AKT 通路主导，而雌二醇能通过上调T细胞PD-1的表达发挥免疫抑制作用。前期研究发现，PD-L1在内异症中高表达，雌二醇能上调PI3K/AKT通路促进内异症的发生。故提出设想：在内异症中雌二醇上调PD-1/PD-L1信号通路从而抑制T细胞功能，引起免疫抑制，导致内膜的异位种植生长。本课题拟从组织、细胞和动物实验三个层次研究该信号通路在内异症中的表达及作用，并探索雌激素对其调节作用及细胞内信号通路。本课题是对内异症发病机制的进一步探索，为抗雌激素和PD-1/PD-L1信号通路拮抗治疗进行理论上的阐述。

子宫内膜异位症是一种免疫调节异常的雌激素依赖性疾病，但是其发生发展机制尚不十分清楚。近期研究发现，PD-1及其配体PD-L1表达于多种免疫细胞，在组织和肿瘤细胞中也有表达，在细胞免疫和肿瘤的免疫逃逸中发挥重要作用。但该通路在内异症中是否异常表达并发挥免疫抑制作用尚未见报道。研究提示 PD-1分子的细胞内信号由PI3K/AKT 通路主导，而雌二醇能通过上调T细胞PD-1的表达发挥免疫抑制作用。前期研究发现，PD-L1在内异症中高表达，雌二醇能上调PI3K/AKT通路促进内异症的发生。在内异症中雌二醇上调PD-1/PD-L1信号通路从而抑制T细胞功能。本课题拟从组织、细胞和动物实验三个层次研究该信号通路在内异症中的表达及作用，并探索雌激素对其调节作用及细胞内信号通路引起免疫抑制，导致内膜的异位种植生长。将子宫内膜异位症经典研究靶点（雌激素）与发病的免疫因素通过 PD-1/PD-L1 信号通路联系起来，在内异症发病机制方面进行了进一步探索，对抗雌激素治疗和PD-1/PD-L1免疫治疗子宫内膜异位症和子宫腺肌病进行理论上的阐述，该研究将为子宫内膜异位性疾病的发生发展机制提供新的思路，并为该疾病的治疗提供新的靶点。