乳腺癌的发生发展与免疫功能紊乱密切相关。共刺激分子PD-1/PD-L1作为负性免疫调节分子，在介导肿瘤免疫逃逸中发挥重要作用。前期系列研究中首次发现共抑制受体PD-1与乳腺癌的发病风险密切相关，部分乳腺癌组织高表达PD-L1。本研究拟通过大量样本信息开展回顾性调查分析高表达PD-L1乳腺癌组织与临床病理指征的相关性，验证PD-L1是否可能作为预测乳腺癌疾病进程和转归及指导治疗的预测性生物标记分子，该相关研究尚属首次提出。并进一步探讨乳腺癌细胞高表达PD-L1的生物学活性及其对肿瘤微环境T细胞亚群侵润的影响，阐明PD-1/PD-L1通路在乳腺癌发生发展中的作用机制，为靶向治疗提供理论依据。

Immune dysfunction is closely associated with the occurrence and development of breast cancer. Co-inhibition plays important roles in regulating T lymphocyte activation and tolerance. In previous a series of researches, we firstly found that Co-inhibition PD-1 was associated with the risk of developing breast cancer and PD-1 ligand (PD-L1) was over-expressed in some breast cancer tissues. To investigate the effect of PD-L1 on tumor escape immune surveillance and progression of breast cancer, we will explore biological activity of breast cancer cells expressing PD-L1, and their interaction with the T cell subsets through detecting the expression of PD-L1 and infiltrating T cell subsets in breast tumor microenvironment. According to these studies, we want to elucidate the mechanisms of the PD-1/PD-L1 pathway in immune escape and immune tolerance of breast cancer. So we expect that the data can provide the scientific theory basis for targeted immunotherapy depending on PD-1/PD-L1 pathway.

乳腺癌是我国妇女常见恶性肿瘤之一,其发生、发展与遗传因素、体内性激素紊乱及机体免疫功能密切相关。共刺激分子PD-1/PD-L1作为负性免疫调节分子，在介导肿瘤免疫逃逸中发挥重要作用。本研究针对乳腺癌临床组织标本及乳腺癌细胞系PD-L1、MDR1及其他相关基因表达水平进行检测，分析乳腺癌组织PD-L1表达与乳腺癌患者临床病理指征及其他预后相关指标的相关性。并进一步通过体外实验探讨了乳腺癌细胞系PD-L1分子表达对各乳腺癌细胞系生物学功能的影响。本研究发现：(1) 247例被检测乳腺癌组织中，PD-L1分子表达高低与患者淋巴转移存在关联；肿瘤细胞PD-L1分子表达高低与组织学分级存在关联；相对于PD-L1分子低表达组，PD-L1分子高表达组人群Her-2阳性率增高。(2) 乳腺癌组织 PD-L1与MDR1表达具有相关性。(3) 体外研究发现IFN-γ上调乳腺癌细胞系MDA-MB-231、T47D等细胞表面PD-L1表达水平；PD-1-Fc 结合MDA-MB-231细胞表面PD-L1后，可通过PI3K/AKT 及MAPK/ERK途径上调细胞MDR1表达水平，从而影响细胞生物学功能。综上所述，本课题证明乳腺癌患者肿瘤组织PD-L1表达水平与患者临床病理特点密切相关；PD-1/PD-L1通路激活通过影响乳腺癌细胞MDR1表达水平改变细胞生物学特点。该研究为PD-L1作为预测乳腺癌疾病进程和转归的预测性生物标记分子提供依据。