Development of innovative cancer immunotherapy targeting metabolites applicable to all patients

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07539
• 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: Yamaguchi University
• Principal Investigator: Shibata Kensuke 山口大学, 大学院医学系研究科, 講師 (50529972)
• Co-Investigator(Kenkyū-buntansha): 山崎 晶 大阪大学, 微生物病研究所, 教授 (40312946)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: T細胞 / 代謝産物 / 免疫療法

Outline of Final Research Achievements

Through recognition of cancer-derived antigens, T cells contribute to killing, metastasis and growth of cancerous cells. Identification of T cell antigens is prerequisite for understanding of cancer biology; however, identity and functions of tumor-associated metabolites recognized by T cells remained unclear. Herein, we demonstrate that a colorectal tumor-associated metabolite, 5-formyl tetrahydrofolate (5-formyl THF) that is generated in the folate synthetic pathway, induces TCR-dependent activation of mouse mucosal-associated invariant T (MAIT) cells. Genetic deletion of Aminomethyltransferase (Amt), encoding a converting enzyme to generate 5-formyl THF, in the colorectal tumor impaired the activation of mouse MAIT cells, whereas Amt-overexpressing colorectal tumors enhanced it. 5-formyl THF had an MAIT cell-dependent anti-tumor activity both in vitro and in vivo.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

MR1T細胞は、2014年に様々な病原体が産生するビタミンB合成中間体を認識し感染防御に働くこと(A.J. Corbett, Nature, 2014)、そしてMR1T細胞特異的検出試薬の開発により特にヒト健常人末梢血中の抗原特異的T細胞の中で最も頻度が高いことが明らかとなり (DI. Godfrey, Na. Rev. Immunol., 2015)、その機能が注目されている。本研究では、世界に先駆けてMR1T細胞が認識するガン抗原を見出し、その抗原を用いた抗ガン効果を確認した。したがって本研究成果は、代謝産物に着目した世界で初めての新規治療法の開発につながることが期待される。