Blocking core fucosylation of PD-1 reduces cell-surface expression and promotes anti-tumor immune responses of T Cells

Research Project

Project/Area Number	17K15451
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Biological pharmacy
Research Institution	Keio University
Principal Investigator	Okada Masahiro 慶應義塾大学, 医学部(信濃町), 特任助教 (30749479)
Project Period (FY)	2017-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000) Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000) Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords	pd-1 / fut8 / core fucose / tumor immunity / PD-1 / Fut8 / 腫瘍免疫 / 糖鎖 / コアフコシル化 / フコース
Outline of Final Research Achievements	PD-1 expression on T cells dampens T cell immune responses against tumors. Uncovering the mechanisms of PD-1 expression contributes to the development of new therapeutics. In this research, by performing the genome wide knockout screen for PD-1 expression, we identified the core fucosylation of PD-1 as one of the mechanism for sustained PD-1 expression. Blockade of core fucosylation reduced PD-1 expression and augmented anti tumor immune responses of T cells.
Academic Significance and Societal Importance of the Research Achievements	PD-1の発現メカニズムの一端を明らかとすることができた。PD-1はT細胞の疲弊を起こす分子の中でも、阻害抗体が多様ながん治療で奏功を示しており、医療においても、がん免疫学においても、重要な標的である。PD-1の発現が、コアフコシル化修飾によって制御されるという新しい機構を提案したことで、新しい治療法の開発や、がん免疫応答の更なる解明につながると期待される。