Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells

Masahiro Okada, Shunsuke Chikuma, Taisuke Kondo, Sana Hibino, Hiroaki Machiyama, Tadashi Yokosuka, Miyako Nakano, Akihiko Yoshimura

研究成果: Article

13 引用 (Scopus)

抄録

Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression. Inhibition of Fut8, a core fucosyltransferase, by genetic ablation or pharmacologic inhibition reduced cell-surface expression of PD-1 and enhanced T cell activation, leading to more efficient tumor eradication. Taken together, our findings suggest that blocking core fucosylation of PD-1 can be a promising strategy for improving anti-tumor immune responses.

元の言語English
ページ(範囲)1017-1028
ページ数12
ジャーナルCell Reports
20
発行部数5
DOI
出版物ステータスPublished - 2017 8 1

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T-cells
Cell death
Tumors
Cell Death
T-Lymphocytes
Neoplasms
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
Chemical activation
Fucosyltransferases
Ablation
Screening
Genome
Ligands
Antibodies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

これを引用

Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells. / Okada, Masahiro; Chikuma, Shunsuke; Kondo, Taisuke; Hibino, Sana; Machiyama, Hiroaki; Yokosuka, Tadashi; Nakano, Miyako; Yoshimura, Akihiko.

:: Cell Reports, 巻 20, 番号 5, 01.08.2017, p. 1017-1028.

研究成果: Article

Okada, Masahiro ; Chikuma, Shunsuke ; Kondo, Taisuke ; Hibino, Sana ; Machiyama, Hiroaki ; Yokosuka, Tadashi ; Nakano, Miyako ; Yoshimura, Akihiko. / Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells. :: Cell Reports. 2017 ; 巻 20, 番号 5. pp. 1017-1028.
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AU - Machiyama, Hiroaki

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AB - Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression. Inhibition of Fut8, a core fucosyltransferase, by genetic ablation or pharmacologic inhibition reduced cell-surface expression of PD-1 and enhanced T cell activation, leading to more efficient tumor eradication. Taken together, our findings suggest that blocking core fucosylation of PD-1 can be a promising strategy for improving anti-tumor immune responses.

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