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

Publication date: 1 August 2017
Source:Cell Reports, Volume 20, Issue 5
Author(s): Masahiro Okada, Shunsuke Chikuma, Taisuke Kondo, Sana Hibino, Hiroaki Machiyama, Tadashi Yokosuka, Miyako Nakano, Akihiko Yoshimura
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.

Graphical abstract

Teaser

Using a genome-wide loss-of-function screening method, Okada et al. identify genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression.


http://ift.tt/2hmFDiw