Using a CRISPR-Cas9-based genome-wide loss-of-function screening method, Okada et al. identified core fucosylation pathway genes involved in surface PD-1 expression in murine T cells. Inhibition of the pathway’s most essential gene (encoding the enzyme Fut8) reduced surface PD-1 expression, enhanced activation, and led to more efficient eradication of tumors in vivo.
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.
Author Info: (1) Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: okada@z5.keio.jp. (2) Department of Micro
Author Info: (1) Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: okada@z5.keio.jp. (2) Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. (3) Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. (4) Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. (5) Department of Immunology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan. (6) Department of Immunology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan. (7) Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-hiroshima, Hiroshima 739-8530, Japan. (8) Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: yoshimura@a6.keio.jp.
