FGFR2 Promotes Expression of PD-L1 in Colorectal Cancer via the JAK/STAT3 Signaling Pathway
FGFR2 Promotes Expression of PD-L1 in Colorectal Cancer via the JAK/STAT3 Signaling Pathway
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DOI：
10.4049/jimmunol.1801199
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发表时间：
2019-05-15
影响因子：
4.4
通讯作者：
Qiu, Hong
中科院分区：
文献类型：
--
作者：
Li, Piao;Huang, Tingting;Qiu, Hong
尽管多学科综合治疗在结直肠癌（CRC）中得到广泛应用，但晚期CRC患者的预后仍然很差。程序性细胞死亡配体1（PD-L1）的免疫治疗阻断是一种有前途的方法。肿瘤细胞或肿瘤微环境细胞表达的跨膜蛋白PD-L1与其受体程序性细胞死亡1（PD-1）结合，诱导免疫抑制信号，降低T细胞增殖，是肿瘤免疫逃逸的重要机制，也是免疫治疗的关键问题。然而，在CRC中对PD-L1表达的调控知之甚少。成纤维细胞生长因子（FGF）受体（FGFR）2通过与FGF结合和二聚化（受体配对）引起酪氨酸激酶结构域启动细胞内信号级联，其参与肿瘤发生和进展。在这项研究中，我们发现PD-L1和FGFR 2在CRC中经常过表达，FGFR 2表达与淋巴结转移、临床分期和不良生存率显著相关。在本研究中，PD-L1表达与CRC中FGFR 2表达呈正相关。在人CRC细胞（SW 480和NCI-H716）中，肿瘤源性活化的FGFR 2通过JAK/STAT 3信号通路诱导PD-L1表达，从而诱导Jurkat T细胞凋亡。FGFR 2还促进了CRC异种移植小鼠模型中PD-L1的表达。我们的研究结果揭示了CRC中PD-L1表达的新机制，从而为逆转CRC中FGFR 2过表达的免疫耐受提供了理论基础。
Although multidisciplinary treatment is widely applied in colorectal cancer (CRC), the prognosis of patients with advanced CRC remains poor. Immunotherapy blocking of programmed cell death ligand 1 (PD-L1) is a promising approach. Binding of the transmembrane protein PD-L1 expressed by tumor cells or tumor microenvironment cells to its receptor programmed cell death 1 (PD-1) induces immunosuppressive signals and reduces the proliferation of T cells, which is an important mechanism of tumor immune escape and a key issue in immunotherapy. However, the regulation of PD-L1 expression is poorly understood in CRC. Fibroblast growth factor (FGF) receptor (FGFR) 2 causes the tyrosine kinase domains to initiate a cascade of intracellular signals by binding to FGFs and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. In this study, we showed that PD-L1 and FGFR2 were frequently overexpressed in CRC, and FGFR2 expression was significantly associated with lymph node metastasis, clinical stage, and poor survival. In the current study, PD-L1 expression was positively correlated with FGFR2 expression in CRC. Tumor-derived-activated FGFR2 induced PD-L1 expression via the JAK/STAT3 signaling pathway in human CRC cells (SW480 and NCI-H716), which induced the apoptosis of Jurkat T cells. FGFR2 also promoted the expression of PD-L1 in a xenograft mouse model of CRC. The results of our study reveal a novel mechanism of PD-L1 expression in CRC, thus providing a theoretical basis for reversing the immune tolerance of FGFR2 overexpression in CRC.