Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma
Changjie Yang, Qiwei Qian, Yudong Zhao, Bingyuan Huang, Ruilin Chen, Qiyu Gong, Hao Ji, Chenchen Wang, Xia Lei, Zhengrui You, Jianjun Zhang, Xiaosong Chen
Abstract
Background and aims The key role of tissue-resident memory T (T RM ) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on T RM 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 T RM cells in HCC. Methods The function and phenotype of intrahepatic CD8 + T RM 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 + T RM cells both in in vitro induction model and in vivo orthotopic HCC mouse model. Results There was an increase in LAG3 expression in CD8 + T RM 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 + T RM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8 + T RM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8 + T RM cell exhaustion, causing tumor immune escape. Conclusions We identified CD8 + T RM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8 + T RM cell function in HCC.