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.

Jun Wang ¹, Miguel F Sanmamed ¹, Ila Datar ², Tina Tianjiao Su ¹, Lan Ji ¹, Jingwei Sun ¹, Ling Chen ³, Yusheng Chen ⁴, Gefeng Zhu ¹, Weiwei Yin ⁵, Linghua Zheng ¹, Ting Zhou ¹, Ti Badri ¹, Sheng Yao ¹, Shu Zhu ¹, Agedi Boto ⁶, Mario Sznol ⁷, Ignacio Melero ⁸, Dario A A Vignali ⁹, Kurt Schalper ², Lieping Chen ¹⁰

Affiliations

1 Department of Immunobiology, Yale University, New Haven, CT 06511, USA.
2 Department of Pathology, Yale University, New Haven, CT 06510, USA.
3 Immunotherapy Institute, Fujian Medical University, Fuzhou, Fujian 350108, China.
4 Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350108, China.
5 Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, China.
6 Department of Immunobiology, Yale University, New Haven, CT 06511, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
7 Department of Medicine (Medical Oncology), Yale University, New Haven, CT 06510, USA.
8 Department of Immunology and Immunotherapy, University of Navarra, Pamplona 31008, Spain.
9 Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
10 Department of Immunobiology, Yale University, New Haven, CT 06511, USA; Immunotherapy Institute, Fujian Medical University, Fuzhou, Fujian 350108, China; Department of Medicine (Medical Oncology), Yale University, New Haven, CT 06510, USA. Electronic address: [email protected].

PMID: 30580966 DOI: 10.1016/j.cell.2018.11.010

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.

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