Cell Reports
Volume 20, Issue 5, 1 August 2017, Pages 1017-1028
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Report
Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells

https://doi.org/10.1016/j.celrep.2017.07.027Get rights and content
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Highlights

  • Core fucosylation pathway genes are involved in cell-surface PD-1 expression

  • Two major sites of core fucosylated N-glycans for PD-1 expression are determined

  • Blocking core fucosylation enhances T cell activation under antigen presentation

  • Anti-tumor immune responses are strengthened by inhibiting fucosylation

Summary

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.

Keywords

PD-1
core fucosylation
CRISPR screen
tumor immunotherapy

Cited by (0)

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Present address: Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan

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Lead Contact