Cell
Volume 176, Issues 1–2, 10 January 2019, Pages 334-347.e12
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Article
Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3

https://doi.org/10.1016/j.cell.2018.11.010Get rights and content
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Highlights

  • FGL1 is a major ligand of LAG-3 that mediates T cell suppression

  • FGL1 is normally released by the liver in low levels but by cancer in high levels

  • Blockade of the FGL1-LAG-3 interaction potentiates anti-tumor immunity

Summary

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

cancer
immunology
immunotherapy
tumor immune-evasion mechanism
LAG-3
FGL1

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