Hepatocyte-derived FGL1 accelerates liver metastasis and tumor growth by inhibiting CD8+ T and NK cells
Fengjia Xi, … , Rui Sun, Yongyan Chen
Fengjia Xi, … , Rui Sun, Yongyan Chen
Published July 8, 2024
Citation Information: JCI Insight. 2024;9(13):e173215. https://doi.org/10.1172/jci.insight.173215.
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Research Article Hepatology Immunology

Hepatocyte-derived FGL1 accelerates liver metastasis and tumor growth by inhibiting CD8+ T and NK cells

Abstract

Fibrinogen-like protein 1 (FGL1) contributes to the proliferation and metabolism of hepatocytes; however, as a major ligand of the immune checkpoint, its role in the liver regional immune microenvironment is poorly understood. Hepatocytes specifically and highly expressed FGL1 under normal physiological conditions. Increases in hepatic CD8+ T and NK cell numbers and functions were found in Fgl1-deficient (Fgl1–/–) mice, but not in the spleen or lymph node, similar to findings in anti-FGL1 mAb–treated wild-type mice. Furthermore, Fgl1 deficiency or anti-FGL1 mAb blockade restrained liver metastasis and slowed the growth of orthotopic tumors, with significantly prolonged survival of tumor-bearing mice. Tumor-infiltrating hepatic CD8+ T and NK cells upregulated the expression of lymphocyte activation gene-3 (LAG-3) and exhibited stronger antitumor activities after anti-FGL1 treatment. The antitumor efficacy of FGL1 blockade depended on cytotoxic T lymphocytes and NK cells, demonstrated by using a cell-deficient mouse model and cell transfer in vivo. In vitro, FGL1 directly inhibited hepatic T and NK cells related to the receptor LAG-3. In conclusion, hepatocyte-derived FGL1 played critical immunoregulatory roles in the liver and contributed to liver metastasis and tumor growth by inhibiting CD8+ T and NK cell functions via the receptor LAG-3, providing a new strategy for liver cancer immunotherapy.

Authors

Fengjia Xi, Haoyu Sun, Hui Peng, Zhexiong Lian, Haiming Wei, Zhigang Tian, Rui Sun, Yongyan Chen

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Figure 6

Blockade of FGL1 delays the progression of liver metastases.

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Blockade of FGL1 delays the progression of liver metastases. (A) Experim...
(A) Experimental protocol for the CRC liver metastasis model used (B–G): On day 0, WT mice were intrasplenically (i.s.) challenged with 2 × 105 MC38 tumor cells and then treated intraperitoneally (i.p.) with 250 μg anti-FGL1 mAb or control rat IgG 4 times 4 days after tumor cell challenge (once every 4 days). (B and C) Representative photograph of livers, number of liver tumor nodules, and maximum tumor volumes at 13 and 21 days after challenge (n = 6/group). Bar, 1 cm. (D) Representative histopathological images of the liver tissues at 17 days after challenge. Bar, 1 mm. (E) Serum levels of ALT and AST and (F) liver weight and hepatosomatic index of mice at 13 days and 21 days after challenge (n = 6/group). (G) Survival of mice challenged with MC38 tumor cells (n = 21 for the rat IgG group; n = 23 for the anti-FGL1 group). (H) Experimental protocol for the melanoma liver metastasis model used in I: On day 0, WT mice were i.s. challenged with 1 × 105 B16-F10 tumor cells and then treated i.p. with 200 μg anti-FGL1 mAb or control rat IgG 3 days after tumor cell challenge 5 times (once every 3 days). (I) Survival of mice challenged with B16-F10 tumor cells (n = 15/group). Data are representative of at least 2 independent experiments (B and C) and pooled from 3 (G) or 2 (I) independent experiments. Comparisons were performed by using 2-tailed unpaired Student’s t test (B and C), 2-way ANOVA followed by Holm-Šídák multiple comparisons test (E and F), and the log-rank (Mantel-Cox) test (G and I). Data are presented as the mean ± SEM (B, C, E, and F). ***P < 0.001, **P < 0.01, *P < 0.05.