Investigating the contribution of potential ligands to the inhibitory function of LAG-3

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Maruhashi Takumi 東京大学, 定量生命科学研究所, 助教 (60743961)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: LAG-3 / 抑制性免疫補助受容体 / 免疫チェックポイント / リガンド / 自己免疫 / がん免疫

Outline of Final Research Achievements

Lymphocyte-activation gene 3 (LAG-3), a potent inhibitory co-receptor, attracts much attention as a promising target of immuno-therapies. However, its functional ligand remains elusive, as several distinct ligands have been identified. Here, we investigated the relative contribution of potential ligands to LAG-3 activity. We found that binding of LAG-3 to stable peptide-MHC class II complex (pMHCII) induced T cell suppression in vitro. Consistently, LAG-3-mediated suppression of fulminant type 1 diabetes and anti-cancer immunity in mice required its engagement with stable pMHCII. These results indicate that stable pMHCII　serves as the functional ligand of LAG-3 to trigger its immuno-inhibitory function.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

すでに使用が開始されているものに加え、がん患者を対象として複数のLAG-3阻害抗体の臨床試験が進行中であるにも関わらず、リガンド分子との結合に対する阻害活性が正確に評価されているとは言えない状況にあった。本研究成果は、LAG-3と安定なpMHCIIとの結合阻害活性が重要な指標であることの科学的根拠となるものであり、安全性と治療効果の高いLAG-3標的薬の開発に貢献すると期待される。