67kDa层粘素受体下调MICA/B诱导胆管癌细胞逃逸NK细胞杀伤的分子机制

Tumor escape play important roles in invasion and metastasis, which causes poor prognosis, and is the key point of medical research. Our previous studies show that 67kDa laminin receptor (67LR) play important roles in cholangiocarcinoma cell escaping from the acquired immunity: it significantly inhibited CD8+T cell-induced lysis through downregulating MHC-I expression and causing T cell apoptosis. However, whether 67LR also affect cancer cell escaping from the natural immunity is not clear. Our preliminary experiment showed that 67LR inhibited NK-mediated lysis of cholangiocarcinoma cells. Combined with previous reports and our data, we postulates that 67LR inhibits NK-mediated lysis via ADAM17-MICA/B pathway in cholantiocarcinoma cells. In present study, we try to invesgate that 67LR downregulates MICA/B by increasing ADAM17 in vitro and in vivo. Then we will study the mechanism by which 67LR regulates ADAM17 by the signaling pathway microarray. The aim of this study is to demonstrate the role and mechanism of 67LR in escaping NK cell-mediated lysis in cholangiocarcinoma cells, and to provide more research evidences for the potential targeted therapy of cholangiocarcinoma.

免疫逃逸是肿瘤转移和复发的重要前提，严重影响预后，是医学研究的重点。我们前期研究发现67kDa层粘素受体（67LR）在胆管癌逃逸获得性免疫中扮演重要角色：通过下调癌细胞MHC-I表达和促进T细胞凋亡诱导癌细胞逃逸CD8+T细胞杀伤，受两项NSFC面上项目资助，已结题。67LR在胆管癌逃逸天然免疫中是否有作用未知。自然杀伤（NK）细胞是肿瘤天然免疫主要的效应细胞，我们预实验发现胆管癌细胞中过表达67LR显著抑制NK细胞介导的杀伤作用。结合文献和预实验结果，我们提出67LR-ADAM17-MICA/B通路诱导胆管癌逃逸NK细胞杀伤的新机制。本项目拟在细胞、临床标本水平研究67LR通过上调ADAM17降低MICA/B表达，抑制NK细胞的杀伤作用；并通过信号通路芯片及阻断剂研究67LR调控ADAM17的机制。本项目拟阐明67LR在胆管癌逃逸天然免疫中的作用，为临床胆管癌免疫靶向治疗提供理论依据。

免疫逃逸是肿瘤转移和复发的重要前提，严重影响预后，是医学研究的重点。我们前期研究发现67kDa层粘素受体（67LR）在胆管癌逃逸获得性免疫中扮演重要角色：通过下调癌细胞MHC-I表达和促进T细胞凋亡诱导癌细胞逃逸 CD8+T细胞杀伤，受两项NSFC面上项目资助，已结题。67LR在胆管癌逃逸天然免疫中是否有作用未知。针对本项目提出的“67LR-ADAM-MICA/B通路诱导胆管癌逃逸NK细胞杀伤的新机制”研究假说，我们经4年研究取得以下成果：（1）临床胆管癌组织中67LR高表达、MICA/B低表达与肿瘤侵袭转移特性显著相关，且与患者预后不良显著相关；（2）胆管癌细胞下调MICA/B表达能显著抑制NK细胞对癌细胞的杀伤作用；（3）胆管癌细胞中67LR通过下调MICA/B表达，抑制NK细胞杀伤癌细胞；（4）67LR可通过ADAM9下调胆管癌细胞MICA/B的表达。本项目阐明了67LR 在胆管癌逃逸天然免疫中的作用，为临床胆管癌免疫靶向治疗提供理论依据。