Development of T cell reprogramming method by metabolic and epigenomic modification

2020 Fiscal Year Final Research Report

• Project/Area Number: 20K20384
• Project/Area Number (Other): 18H05376 (2018-2019)
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund (2020); Single-year Grants (2018-2019)
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Keio University
• Principal Investigator: Yoshimura Akihiko 慶應義塾大学, 医学部(信濃町), 教授 (90182815)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Keywords: 免疫学 / 免疫記憶 / 腫瘍免疫 / サイトカイン / 代謝

Outline of Final Research Achievements

T cell exhaustion not only reduces the effectiveness of tumor immunity, but also causes resistance to checkpoint inhibitor therapy. However, the molecular mechanisms of T cell exhaustion have only just begun to be elucidated. In this study, we found that the NR4a family of nuclear receptors plays a central role in the exhaustion of CD8+ T cells. Furthermore, we found that deletion of NR4a resulted in a strong anti-tumor effect. On the other hand, as a method to reprogram exhausted T cells into young memory, we showed that activated T cells such as CAR-T can be converted into stem cell memory T (Tscm)-like cells (iTscm) by co-culturing with Notch ligand-expressing OP9 cells. This mechanism is now being elucidated.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

がんにおける免疫チェックポイント阻害療法はノーベル賞を受賞したこともあって大きな注目を集めている。しかし療法抵抗性の患者も多く、より強力な免疫療法の開発が望まれている。腫瘍免疫の効果を減弱させる大きな要因のひとつはがんを攻撃するT細胞疲弊化である。我々のグループは疲弊化を起こす原因遺伝子としてNR4aを発見し、さらに疲弊化したT細胞をより若いメモリー幹細胞にリプログラム方法を開発した。このメカニズムを解明できればがんの免疫療法の可能性を大きく広げることになる。