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

Cell Rep. 2017 Aug 1;20(5):1017-1028. doi: 10.1016/j.celrep.2017.07.027.


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: CRISPR screen; PD-1; core fucosylation; tumor immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Fucosyltransferases* / genetics
  • Fucosyltransferases* / immunology
  • Gene Expression Regulation, Neoplastic / immunology*
  • Genome-Wide Association Study
  • Glycosylation
  • Humans
  • Immunity, Cellular*
  • Lymphocyte Activation
  • Mice
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / immunology
  • Neoplasms, Experimental* / genetics
  • Neoplasms, Experimental* / immunology
  • Neoplasms, Experimental* / pathology
  • Programmed Cell Death 1 Receptor* / genetics
  • Programmed Cell Death 1 Receptor* / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology


  • Neoplasm Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Fucosyltransferases
  • Glycoprotein 6-alpha-L-fucosyltransferase