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

• Published in: Cell reports (Cambridge) Vol. 20; no. 5; pp. 1017 - 1028
• Main Authors: Okada, Masahiro, Chikuma, Shunsuke, Kondo, Taisuke, Hibino, Sana, Machiyama, Hiroaki, Yokosuka, Tadashi, Nakano, Miyako, Yoshimura, Akihiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017; Elsevier
• Subjects: Animals; core fucosylation; CRISPR screen; 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; PD-1; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; tumor immunotherapy; CRISPR screen; core fucosylation; PD-1; tumor immunotherapy
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •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 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.