LAIR1 通过 GSK-3β/β-catenin/MYC/PD-L1 通路介导肝癌细胞对 T 细胞的抵抗。
LAIR1-mediated resistance of hepatocellular carcinoma cells to T cells through a GSK-3β/β-catenin/MYC/PD-L1 pathway.
机构信息
Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China.
出版信息
Cell Signal. 2024 Mar;115:111039. doi: 10.1016/j.cellsig.2024.111039. Epub 2024 Jan 8.
BACKGROUND
An increasing number of studies have reported the involvement of oncogenes in the regulation of the immune system. LAIR1 is an immunosuppressive molecule and its role in immune-related diseases has been mainly reported. To date, it is unclear whether LAIR1 in tumor cells is involved in immune regulation. Therefore, the aim of this study was to investigate the role of LAIR1 in the immune microenvironment of hepatocellular carcinoma (HCC) to seek the novel therapeutic discoveries.
METHODS
Tumor Immune Dysfunction and Exclusion database was used to predict the response of LAIR1 expression to immune checkpoint blockade. CD8 T cells were co-cultured with HCC cells, and the killing efficiency of leukocytes on HCC cells was detected by flow cytometry. Flow cytometry was also used to detect the expression of inhibitory receptors. In addition, Western blot, immunofluorescence, and nucleus/cytoplasm fractionation experiments were performed to explore the molecular mechanisms by which LAIR1 created a suppressive tumor microenvironment.
RESULTS
LAIR1 expression in HCC was associated with worse immune prognosis and T-cell dysfunction. HCC cells overexpressing LAIR1 co-cultured with CD8 T cells induced exhaustion of latter. Mechanism studies indicated that LAIR1 in HCC cells up-regulated the phosphorylation of β-catenin by inducing the phosphorylation of GSK-3β, leading to the impairment of the expression and the nuclear localization signal of β-catenin. Low β-catenin expression and nuclear localization signal inhibited MYC-mediated PD-L1 expression. Therefore, PD-L1 up-regulated by LAIR1 caused the exhaustion of infiltrating CD8 T cells in HCC, which aggravated the malignant progression of HCC.
CONCLUSION
LAIR1 increased PD-L1 expression through the GSK-3β/β-catenin/MYC/PD-L1 pathway and promoted immune evasion of HCC cells. Targeted inhibition of LAIR1 helped to enhance the immune killing effect of CD8 T cells in HCC.
背景
越来越多的研究报告称癌基因参与了免疫系统的调节。LAIR1 是一种免疫抑制分子，其在免疫相关疾病中的作用主要被报道。迄今为止，尚不清楚肿瘤细胞中的 LAIR1 是否参与免疫调节。因此，本研究旨在探讨 LAIR1 在肝细胞癌（HCC）免疫微环境中的作用，寻求新的治疗发现。
方法
使用肿瘤免疫功能障碍和排斥数据库来预测 LAIR1 表达对免疫检查点阻断的反应。将 CD8 T 细胞与 HCC 细胞共培养，并用流式细胞术检测白细胞对 HCC 细胞的杀伤效率。流式细胞术还用于检测抑制性受体的表达。此外，还进行了 Western blot、免疫荧光和核/细胞质分离实验，以探讨 LAIR1 如何在肿瘤微环境中产生抑制作用的分子机制。
结果
HCC 中 LAIR1 的表达与免疫预后不良和 T 细胞功能障碍有关。与 CD8 T 细胞共培养的过表达 LAIR1 的 HCC 细胞诱导后者衰竭。机制研究表明，HCC 细胞中的 LAIR1 通过诱导 GSK-3β磷酸化而上调 β-连环蛋白的磷酸化，导致 β-连环蛋白的表达和核定位信号受损。低 β-连环蛋白表达和核定位信号抑制了 MYC 介导的 PD-L1 表达。因此，LAIR1 上调的 PD-L1 导致 HCC 浸润性 CD8 T 细胞衰竭，从而加重 HCC 的恶性进展。
结论
LAIR1 通过 GSK-3β/β-连环蛋白/MYC/PD-L1 通路增加 PD-L1 的表达，促进 HCC 细胞的免疫逃逸。靶向抑制 LAIR1 有助于增强 CD8 T 细胞在 HCC 中的免疫杀伤作用。
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