Cell https://doi.org/10.1016/j.cell.2018.11.010 (2018)

MHC class II is considered the canonical ligand for the inhibitory receptor LAG-3. In Cell, Chen and colleagues identify the fibrinogen family protein FGL1 as a major ligand for LAG-3. The FGL1–LAG-3 interaction is conserved in human and mouse, is specific to FGL1, involves the fibrinogen-like domain of FGL1 and the D1-D2 domain of LAG-3 and is independent of MHC class II. Fgl1–/– mice develop spontaneous autoimmunity with age. Similar to Lag3–/– mice, Fgl1–/– mice control the growth of inoculated tumors better than wild-type mice do, in a manner dependent on CD8+ T cells and CD4+ T cells. Antibodies to LAG-3 are not protective against tumors in the Fgl1–/– mice. FGL1 mRNA, which is normally expressed only in liver and pancreas, is upregulated in a variety of human solid tumors, and high expression of FGL1 in the plasma of patients with melanoma or lung cancer is associated with decreased survival in response to therapy with antibody to PD-1. These results indicate that the FGL1–LAG-3 interaction represents a mechanism of tumor evasion.