Mechanism of graft versus leukemia effect and its application to adoptive immunotherapy

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07175
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Hiroshima University
• Principal Investigator: KAWASE TAKAKAZU 広島大学, 原爆放射線医科学研究所, 助教 (30463194)
• Co-Investigator(Kenkyū-buntansha): 一戸 辰夫 広島大学, 原爆放射線医科学研究所, 教授 (80314219)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: T細胞受容体 / 次世代シークエンサー / １細胞単離解析 / 幹細胞様メモリーT細胞

Outline of Final Research Achievements

Recently, immunologic significance of stem cell memory (SCM) T-cell subset has been increasingly recognized, especially as original cell source for adoptive T-cell therapy. To comprehensively elucidate TCR clonotypes of SCM T-cells, we performed ultra-in-depth analysis of cytomegalovirus (CMV)-specific TCR repertoire in various functional T-cell subsets using next generation sequencing (NGS) and single cell cloning of TCRs. CMV pp65-specific T-cells in circulating blood of healthy donors were extremely oligoclonal and most of the dominant TCRs had higher affinity to pp65-tetramer. Intriguingly, these dominant CMV-specific TCR clonotypes were highly shared among different individuals and were also present in CMV-seronegative donors. Notably, TCR diversity of SCM T-cells was significantly lower than that of CM and EM T-cell repertoire. These results suggest that SCM T-cell subset functions as a reservoir of highly-shared and highly-functional memory T-cells.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究をとおして、T細胞を網羅的かつ、T細胞受容体のα、βのペアの情報を組み合わせて解析する技術を開発することができた。この技術を用いて、幹細胞様メモリーT細胞に免疫学的に重要な抗原特異的T細胞が多く存在することが明らかとなり、幹細胞様メモリーT細胞が単にナイーブT細胞からエフェクターT細胞へ向かう文化の一段階ではなく、免疫学的により重要な分画であることを示唆する結果を得た。この技術を用いたかいせきにより、養子免疫療法への応用を見据えた、造血幹細胞移植後の再発を抑制するT細胞受容体、がん抗原特異的T細胞受容体データベースの構築が進んでいる。