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Abstract：
The key role of tissue-resident memory T (TRM) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on TRM cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) is a classical ligand of LAG-3 and can promote T cell exhaustion in tumors. Here, we excavated the effect of FGL1-LAG3 regulatory axis on TRM cells in HCC.
The function and phenotype of intrahepatic CD8+ TRM cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8+ TRM cells both in in vitro induction model and in vivo orthotopic HCC mouse model.
There was an increase in LAG3 expression in CD8+ TRM cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8+ TRM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8+ TRM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8+ TRM cell exhaustion, causing tumor immune escape.
We identified CD8+TRM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8+ TRM cell function in HCC.
The function and phenotype of intrahepatic CD8+ TRM cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8+ TRM cells both in in vitro induction model and in vivo orthotopic HCC mouse model.
There was an increase in LAG3 expression in CD8+ TRM cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8+ TRM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8+ TRM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8+ TRM cell exhaustion, causing tumor immune escape.
We identified CD8+TRM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8+ TRM cell function in HCC.
摘要：
组织驻留记忆T（TRM）细胞在肝细胞癌（HCC）的免疫调节中的关键作用已被研究和报道，但肿瘤微环境对TRM细胞的调控机制尚不清楚。淋巴细胞激活基因3（LAG-3）是一种有前途的下一代免疫检查点，由于肿瘤微环境中持续的抗原暴露而连续表达。纤维蛋白原样蛋白1（FGL1）是LAG-3的经典配体，可以促进肿瘤中的T细胞衰竭。这里,我们挖掘了FGL1-LAG3调节轴对肝癌TRM细胞的影响。
使用多色流式细胞术分析了35例HCC患者肝内CD8TRM细胞的功能和表型。使用80例HCC患者的组织微阵列，我们进行了预后分析.此外，我们在体外诱导模型和体内原位HCC小鼠模型中研究了FGL1对CD8TRM细胞的抑制作用。
在晚期HCC的CD8+TRM细胞中LAG3表达增加；此外，FGL1水平与CD103表达呈负相关，与HCC不良预后相关。高CD8+TRM细胞比例的患者有更好的结果，FGL1-LAG3结合可导致肿瘤中CD8+TRM细胞耗尽，表明其作为肝癌免疫检查点治疗靶点的潜力。肝癌中FGL1表达增加可能导致CD8+TRM细胞衰竭，导致肿瘤免疫逃逸。
我们将CD8+TRM细胞确定为潜在的免疫治疗靶标，并报道了FGL1-LAG3结合对HCC中CD8+TRM细胞功能的影响。
使用多色流式细胞术分析了35例HCC患者肝内CD8TRM细胞的功能和表型。使用80例HCC患者的组织微阵列，我们进行了预后分析.此外，我们在体外诱导模型和体内原位HCC小鼠模型中研究了FGL1对CD8TRM细胞的抑制作用。
在晚期HCC的CD8+TRM细胞中LAG3表达增加；此外，FGL1水平与CD103表达呈负相关，与HCC不良预后相关。高CD8+TRM细胞比例的患者有更好的结果，FGL1-LAG3结合可导致肿瘤中CD8+TRM细胞耗尽，表明其作为肝癌免疫检查点治疗靶点的潜力。肝癌中FGL1表达增加可能导致CD8+TRM细胞衰竭，导致肿瘤免疫逃逸。
我们将CD8+TRM细胞确定为潜在的免疫治疗靶标，并报道了FGL1-LAG3结合对HCC中CD8+TRM细胞功能的影响。
