Targeting glycosylated PD-1 induces potent anti-tumor immunity

Cancer Research
Linlin SunMien-Chie Hung

Abstract

Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T-cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using monoclonal antibodies, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The monoclonal antibody STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing anti-tumor immunity. Together these findings provide novel insights into the functional significance of PD-1 glycosylation and...Continue Reading

Citations

Aug 28, 2020·Frontiers in Immunology·Shin Foong Ngiow, Arabella Young
Jul 6, 2020·Journal of Biomedical Science·Ying-Nai WangMien-Chie Hung
Oct 7, 2020·Journal for Immunotherapy of Cancer·Natalia Rodrigues MantuanoHeinz Läubli
Jun 10, 2021·Communications Biology·Pottayil G SasikumarMurali Ramachandra
Jun 3, 2021·Cells·Ruoxuan SunSeung-Oe Lim
Oct 20, 2020·Journal of Proteome Research·Julius BenickyRadoslav Goldman

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