Basic research for the development of a novel CAR-adaptor T cells by an advanced imaging system

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03600
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Tokyo Medical University
• Principal Investigator: Yokosuka Tadashi 東京医科大学, 医学部, 主任教授 (10359599)
• Co-Investigator(Kenkyū-buntansha): 矢那瀬 紀子 東京医科大学, 医学部, 講師 (10210303) ; 町山 裕亮 東京医科大学, 医学部, 講師 (40704606)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: がん免疫 / 細胞療法 / T細胞 / 分子イメージング / シグナル伝達 / キメラ抗原受容体

Outline of Final Research Achievements

In this project, we established a brand-new and innovative imaging system combining antigen-presenting planar lipid bilayers and super-resolution microscopies and performed single cell analyses for the human CD19 chimeric antigen receptor T (hCD19 CAR-T) cells, recently used in a developing adoptive-transfer cancer immunotherapy. In a ligand-binding fashion, the hCD19 CAR gathers together and forms a functional signalosome, “hCD19 CAR microcluster”, recruited by both various signaling molecules in the downstream of TCRs and a great deal of tyrosine-phosphorylated proteins. We demonstrated that the hCD19 CAR microcluster could determine the CAR-T cell activation, cytotoxic function and CAR-T cell survival, collaborating with TCR signaling.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

ノーベル医学生理学賞受賞を機にがん免疫療の臨床応用や研究は急速に進んでおり、中でもCAR-T細胞療法の技術革新は目覚ましい。一方、臨床応用が先行しその作用機序の解明が未解決な点など、残された課題も多く存在する。本研究で行った革新的イメージングシステムの構築、CAR-T細胞のシグナル伝達経路の可視化、CAR-T細胞のがん細胞傷害機構の解明、細胞内シグナル伝達分子を導入した新たなCARの提案からは、より高い細胞傷害機能と安全性を兼ね備えた次世代CAR-T細胞の創出が期待できる。