Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.

Abstract

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.

• Authors: Jun Wang, Miguel F Sanmamed, Ila Datar, Tina Tianjiao Su, Lan Ji, Jingwei Sun, Ling Chen, Yusheng Chen, Gefeng Zhu, Weiwei Yin, Linghua Zheng, Ting Zhou, Ti Badri, Sheng Yao, Shu Zhu, Agedi Boto, Mario Sznol, Ignacio Melero, Dario A A Vignali, Kurt Schalper, Lieping Chen
• Journal: Cell (Cell) Vol. 176 Issue 1-2 Pg. 334-347.e12 (01 10 2019) ISSN: 1097-4172 [Electronic] United States
• PMID: 30580966 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• FGL1 protein, human
• Histocompatibility Antigens Class II
• Ligands
• Neoplasm Proteins
• Fibrinogen
• Lymphocyte Activation Gene 3 Protein

Topics

• Animals
• Antigens, CD (immunology, metabolism)
• Cell Line
• Fibrinogen (immunology, metabolism)
• Genes, MHC Class II (genetics, immunology)
• Histocompatibility Antigens Class II (genetics, immunology, metabolism)
• Humans
• Immunotherapy
• Ligands
• Liver (metabolism)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasm Proteins (genetics, metabolism, physiology)
• Neoplasms (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Lymphocyte Activation Gene 3 Protein