Key Laboratory of Immune Response and Immunotherapy, the Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Hefei, China.
JCI Insight. 2024 May 23;9(13):e173215. doi: 10.1172/jci.insight.173215.
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.
纤维蛋白原样蛋白 1（FGL1）有助于肝细胞的增殖和代谢；然而，作为免疫检查点的主要配体，其在肝脏局部免疫微环境中的作用尚不清楚。在正常生理条件下，肝细胞特异性且高表达 FGL1。在 Fgl1 缺陷（Fgl1-/-）小鼠中发现肝 CD8+T 和 NK 细胞数量和功能增加，但在脾或淋巴结中未发现，这与抗 FGL1 mAb 处理的野生型小鼠的发现相似。此外，Fgl1 缺陷或抗 FGL1 mAb 阻断抑制肝转移并减缓原位肿瘤的生长，荷瘤小鼠的生存时间显著延长。肿瘤浸润性肝 CD8+T 和 NK 细胞上调淋巴细胞活化基因 3（LAG-3）的表达，在抗 FGL1 治疗后表现出更强的抗肿瘤活性。FGL1 阻断的抗肿瘤疗效取决于细胞毒性 T 淋巴细胞和 NK 细胞，这通过使用细胞缺陷小鼠模型和体内细胞转移得到证实。体外，FGL1 直接抑制与受体 LAG-3 相关的肝 T 和 NK 细胞。总之，肝细胞来源的 FGL1 在肝脏中发挥关键的免疫调节作用，通过受体 LAG-3 抑制 CD8+T 和 NK 细胞功能，促进肝转移和肿瘤生长，为肝癌免疫治疗提供了新策略。
