肿瘤源性HLA-G诱导的NK无能在促进胰腺癌肝转移中的相关机制研究

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer worldwide. Clinically, hepatic metastasis of .PDAC is the most common phenomenon, and finally leads to the failure of treatment. Therefore, it is very necessary to elucidate the mechanism of hepatic metastasis of PDAC and explore the potential targets. The NK cell is an important defense mechanism of the host in tumor immune surveillance. The liver is the organ which most enriched in NK cells. PDAC is most likely to metastasize to the liver, which suggests the dysfunction of natural immune in liver. We found previously: 1. In a study of large sample of PDAD patients ,we found the abnormal activation of NK cells. 2 In PDAC patients, high level of HLA-G in tumor tissues or in peripheral blood promote tumor invasion and metastasis.3 HLA-G associated with tumor immune escape, and led to poor prognosis. Therefore, we hypothesized that PDAC tumor derived HLA-G induced abnormal activation of NK cells, and lead to the dysfunction of immune surveillance, especially forming a tumor permissive microenvironment in in liver. This project attempts to investigate the crosstalk of tumor and immune microenvironment, focusing on the pathway of HLA-G/NK. To clarify the mechanism of tumor immune escape. The work may explore the novel mechanism of tumor immune escape, and could provide a potential therapeutic strategy.

胰腺癌进展快，预后极差，在疾病起始时常伴有远处转移，最常见是肝转移。NK细胞的重要功能是杀伤肿瘤、抵御肿瘤转移，是肿瘤免疫监视的重要防御力量。而肝脏是人体NK细胞最富集的脏器，胰腺癌极易肝转移的现象，提示肝脏局部微环境中免疫监视功能异常，特别是NK细胞功能的异常。我们前期研究发现：胰腺癌患者NK细胞数明显升高，异常激活，却是无功能状态。胰腺癌肿瘤高表达HLA-G，抑制肿瘤免疫，促进了肿瘤转移，与不良预后相关。而HLA-G可通过NKG2A受体抑制NK细胞而导致无能。因此我们推测胰腺癌高表达HLA-G，异常激活NK细胞并导致无能，失去免疫监视功能，并且在肝脏内诱导形成免疫耐受亚群，形成利于肿瘤转移的微环境（转移小生境），促进肿瘤肝转移的形成。本课题试图从肿瘤/免疫微环境间的交互作用，研究肿瘤免疫逃逸和胰腺癌特异性器官转移的机制，并探索可能的干预靶点，具有重要的现实意义和理论价值。