Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma

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.

Keywords: exhaustion; granzyme B; hepatocellular carcinoma; lymphocyte activation gene 3; tissue-resident memory T cells.