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

Background and aimsThe 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. MethodsThe 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. ResultsThere 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. ConclusionsWe 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.