GDNF secreted by nerves enhances PD-L1 expression via JAK2-STAT1 signaling activation in HNSCC
GDNF secreted by nerves enhances PD-L1 expression via JAK2-STAT1 signaling activation in HNSCC
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神经分泌的 GDNF 通过 JAK2-STAT1 信号激活增强 HNSCC 中 PD-L1 的表达
DOI：
10.1080/2162402x.2017.1353860
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Ji, Tong
中科院分区：
文献类型：
--
作者：
Lin, Chengzhong;Cao, Wei;Ji, Tong
程序性死亡配体1(PD-L1)是一种重要的免疫抑制因子，通过与其受体PD-1结合，导致免疫细胞功能障碍和免疫系统逃逸。然而，PD-L1在生长因子刺激下表达的机制尚不清楚。在这里，我们展示了胶质细胞系衍生神经营养因子(GDNF)在头颈部鳞状细胞癌(HNSCC)中上调PD-L1表达的新作用。应用TCGA数据库生物信息学分析和免疫组织化学方法检测145例HNSCC中PD-L1、GDNF的表达及其与神经侵袭(PNI)状态的相关性。用流式细胞仪、Western印迹和实时荧光定量聚合酶链式反应检测GNDF孵育后HNSCC细胞中PD-L1的表达。用抗体阵列分析GDNF激活的细胞信号通路，并用特定的信号抑制剂阻断癌细胞株。在HNSCC标本中，PNI阳性的癌细胞中PD-L1的表达显著升高，且PD-L1的表达升高与GDNF水平显著相关。GDNF不仅增强了背根神经节与癌细胞共培养的癌细胞PNI，而且通过JAK2-STAT1信号通路诱导PD-L1的表达。此外，JAK2抑制剂可减弱GDNF诱导的PD-L1，并增强肿瘤细胞对NK细胞杀伤的敏感性。我们的发现提供了临床上新的证据，证明神经源性GDNF可以增加神经周围壁龛周围癌细胞中PD-L1的水平，并且调节信号对于癌细胞逃避神经-癌症微环境中的免疫监视至关重要。
Programmed death ligand 1 (PD-L1) functions as a key immune inhibitory factor by binding with its receptor, programmed death 1 (PD-1), to induce immune cell dysfunction and escape of the immune system. However, the mechanisms of PD-L1 expression under growth factor stimulation are not well characterized. Here, we demonstrate a novel role for glial cell line-derived neurotrophic factor (GDNF) in upregulating PD-L1 expression in head and neck squamous cell carcinoma (HNSCC). The expression and correlation of PD-L1, GDNF and perineural invasion (PNI) status were evaluated by bioinformatics analysis of TCGA database and IHC assays from 145 HNSCC patients. PD-L1 expression was investigated by flow cytometry, Western blot and real-time PCR analyses in HNSCC cells after GNDF incubation. The cell signaling pathways activated by GDNF were analyzed with an antibody array and blocked by specific signaling inhibitors in cancer cell lines. PD-L1 expression was significantly higher in cancer cells that exhibited PNI in the HNSCC specimens, and elevated PD-L1 expression was significantly correlated with GDNF levels. GDNF not only enhanced cancer cell PNI in a co-culture of dorsal root ganglions and cancer cells but also had a potent role in inducing PD-L1 expression through the JAK2-STAT1 signaling pathway. Moreover, a JAK2 inhibitor attenuated GDNF-induced PD-L1 and enhanced tumor cell susceptibility to NK cell killing. Our findings provide clinically novel evidence that nerve-derived GDNF can increase PD-L1 levels in cancer cells around the perineural niche and that regulatory signaling is critical for cancer cell escape from immune surveillance in the nerve-cancer microenvironment.