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

Cell. 2019 Jan 10;176(1-2):334-347.e12. doi: 10.1016/j.cell.2018.11.010. Epub 2018 Dec 20.

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.

Keywords: FGL1; LAG-3; cancer; immunology; immunotherapy; tumor immune-evasion mechanism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antigens, CD
  • CD223 antigen
  • FGL1 protein, human
  • Histocompatibility Antigens Class II
  • Ligands
  • Neoplasm Proteins
  • Fibrinogen