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.
摘要:
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,它在肝脏局部免疫微环境中的作用知之甚少。肝细胞在正常生理条件下特异性和高度表达FGL1。在Fgl1缺陷(Fgl1-/-)小鼠中发现肝CD8T和NK细胞数量和功能的增加,但不在脾脏或淋巴结中,与抗FGL1mAb处理的野生型小鼠的发现相似。此外,Fgl1缺乏或抗FGL1mAb阻断抑制肝转移并减缓原位肿瘤的生长,显著延长荷瘤小鼠的生存期。肿瘤浸润肝CD8T和NK细胞上调淋巴细胞活化基因3(LAG-3)的表达,并在抗FGL1治疗后表现出更强的抗肿瘤活性。FGL1阻断的抗肿瘤疗效依赖于细胞毒性T淋巴细胞和NK细胞,通过使用细胞缺陷小鼠模型和体内细胞转移来证明。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在肝脏中发挥重要的免疫调节作用,并通过受体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的策略。