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

Research output: Contribution to journalArticle

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Abstract

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.

LanguageEnglish
Pages1017-1028
Number of pages12
JournalCell Reports
Volume20
Issue number5
DOIs
StatePublished - 2017 Aug 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

Keywords

  • core fucosylation
  • CRISPR screen
  • PD-1
  • tumor immunotherapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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.

In: Cell Reports, Vol. 20, No. 5, 01.08.2017, p. 1017-1028.

Research output: Contribution to journalArticle

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. In: Cell Reports. 2017 ; Vol. 20, No. 5. pp. 1017-1028
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