Using molecular imaging, analysis of LAG-3-mediated suppression of anti-tumor immune response

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07718
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Wakamatsu Ei 東京医科大学, 医学部, 講師 (40632617)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: LAG-3 / T細胞 / トロゴサイトーシス / MHC class II / 免疫チェックポイント分子 / 腫瘍免疫

Outline of Final Research Achievements

Blockade of PD-1 and/or CTLA4 has shown outstanding efficacy for tumor immunotherapy, and LAG-3 blocking antibodies have been proposed as the next generation of immune checkpoint inhibitors. However, the mechanism of LAG-3-mediated suppression is still poorly understood. Here, by utilizing high-resolution molecular imaging, we found that LAG-3-bound MHC class II (MHC-II) molecules on antigen-presenting cells (APCs) were gathered at the center of an immunological synapse in both CD4 and CD8 T cells, leading to the trogocytosis of MHC-II by the ectodomain of LAG-3 through clathrin-dependent endocytosis. By using this mechanism, LAG-3-expressing T cells reduced the number of MHC-II molecules on APCs, thus attenuating their antigen-presentation function, and impaired CD4 T cell activation both in vitro and in vivo. These data reveal a novel mechanism of indirect suppression of CD4 T cells by LAG-3-mediated trogocytosis, which could be the next candidate for tumor immunotherapy.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

LAG3を含めた免疫チェックポイント分子の多くが、分子機構や作用機序に関して十分な理解がなされておらず、臨床応用のみが先行している。そのため、患者選定や複合免疫療法などの可能性を考慮する際の科学的な根拠は十分ではない。本研究では、分子イメージング法という新たな視点からLAG3を研究することで、LAG3発現T細胞の新たな機能を明らかにした。これらの結果は抗LAG3抗体はCD8 T細胞の直接的な活性化、CD4 T細胞を介した間接的な活性化によって抗腫瘍免疫応答を亢進させている可能性が示唆している。このように抗LAG3抗体の免疫賦活化機構を提案できたことは、学術的、社会的に非常に意義がある。