Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG3
Lymphocyte-activation gene 3 (LAG3) 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 LAG3. Here, we demonstrate that fibrinogen-like p...
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Published in | Cell Vol. 176; no. 1-2; pp. 334 - 347.e12 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
20.12.2018
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Online Access | Get full text |
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Summary: | Lymphocyte-activation gene 3 (LAG3) 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 LAG3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG3 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/LAG3 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.
In Brief
FGL1 is identified as a major ligand for the inhibitory receptor LAG3 and its blockade can potentiate anti-tumor T cell responses |
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Bibliography: | Conceptualization, J.W.,M.F.S.,L.C.; Methodology, J.W., M.F.S., I.D., T.T.S., L.J., L.C., J.S., S.Y., G.Z.; Software, J.W., M.F.S., T.T.S., I.D., W.Y.,T.Z., S.Z.; Formal Analysis, J.W., M.F.S., T.T.S., I.D., W.Y., A.B.,L.C.; Investigation, J.W., M.F.S., T.T.S., L.J., I.D., L.C., J.S., T.B.; Resources, L.Z., T.Z., S.Y., M.S., I.M., D.A.A.V., Y.C., K.S., L.C., Writing-Original Draft, J.W., L.C.; Review & Editing, J.W., L.C., T.T.S., M.F.S., D.A.A.V., M.S., I.M., K.S.; Visualization, J.W., M.F.S., L.C.; Supervision, L.C.; Project Administration, J.W., L.C.; Funding Acquisition, L.C. Author Contributions |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2018.11.010 |