DCDC2/ENO1轴通过激活FGL1-LAG3检查点促进肝内胆管癌的肿瘤进展和免疫逃逸。
The DCDC2/ENO1 axis promotes tumor progression and immune evasion in intrahepatic cholangiocarcinoma via activating FGL1-LAG3 checkpoint.
作者信息
Wan Wenze, Li Yuan, Sun Wentao, Cheng Zewei, Ma Fen, Shen Sheng, Liu Houbao, Zhang Jiwei
机构信息
Department of Biliary Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
出版信息
J Exp Clin Cancer Res. 2025 Jun 18;44(1):177. doi: 10.1186/s13046-025-03436-1.
BACKGROUND & AIMS: ICC is a malignant tumor that originates from the intrahepatic bile ducts with insidious symptoms and a poor prognosis. Early diagnosis methods and therapeutic targets are urgently needed for ICC.
METHODS
We utilized a comprehensive set of analytical techniques to elucidate the role and mechanisms of DCDC2 in ICC. Our study included protein microarrays, transcriptome analysis, functional assays, immunofluorescence, dual-luciferase reporter assays, as well as xenograft models and humanized PBMC models.
RESULTS
Our study demonstrates that elevated levels of anti-DCDC2 autoantibodies in the serum of ICC patients indicate its potential utility as a diagnostic biomarker. Comprehensive in vitro and in vivo analyses reveal that DCDC2 promotes ICC proliferation, metastasis, and immune evasion. Mechanistically, DCDC2 stabilizes ENO1, resulting in enhanced AKT phosphorylation and increased expression of FGL1. Notably, elevated FGL1 levels significantly impair CD8 T cell functionality via the FGL1-LAG3 axis.
CONCLUSION
Our findings position anti-DCDC2 autoantibody as a promising diagnostic biomarker for ICC, associated with poor prognostic outcomes, and elucidate its critical role in tumor growth and immune evasion through its interaction with ENO1.
背景与目的
肝内胆管癌（ICC）是一种起源于肝内胆管的恶性肿瘤，症状隐匿，预后较差。ICC迫切需要早期诊断方法和治疗靶点。
方法
我们运用了一系列综合分析技术来阐明双皮质素样激酶2（DCDC2）在ICC中的作用及机制。我们的研究包括蛋白质微阵列、转录组分析、功能测定、免疫荧光、双荧光素酶报告基因测定，以及异种移植模型和人源化外周血单核细胞（PBMC）模型。
结果
我们的研究表明，ICC患者血清中抗DCDC2自身抗体水平升高表明其作为诊断生物标志物的潜在效用。全面的体外和体内分析表明，DCDC2促进ICC的增殖、转移和免疫逃逸。从机制上讲，DCDC2使烯醇化酶1（ENO1）稳定，导致AKT磷酸化增强和纤维胶凝蛋白1（FGL1）表达增加。值得注意的是，FGL1水平升高通过FGL1 -淋巴细胞活化基因3（LAG3）轴显著损害CD8 T细胞功能。
结论
我们的研究结果表明抗DCDC2自身抗体是一种有前景的ICC诊断生物标志物，与不良预后相关，并通过其与ENO1的相互作用阐明了其在肿瘤生长和免疫逃逸中的关键作用。
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