Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity
- 10 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (11), 2298-2310
- https://doi.org/10.1158/0008-5472.can-19-3133
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 offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy.Keywords
Funding Information
- National Natural Science Foundation of China (81972186, 31301160)
- MIRA (RP160710)
- Breast Cancer Research Foundation (BCRF-17-069)
- National Institutes of Health (CCSG CA016672)
- T32 training (5T32CA186892)
- YingTsai Young Scholar (CMU108-YTY-02)
- Ministry of Education (1040082029B)
- Ministry of Science and Technology (MOST 109-2314-B-001-002)
This publication has 27 references indexed in Scilit:
- In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human PrimatesCancer Immunology Research, 2014
- Molecular mechanisms of T cell co-stimulation and co-inhibitionNature Reviews Immunology, 2013
- Vertebrate protein glycosylation: diversity, synthesis and functionNature Reviews Molecular Cell Biology, 2012
- Turning 'sweet' on immunity: galectin–glycan interactions in immune tolerance and inflammationNature Reviews Immunology, 2009
- PD‐1 signaling in primary T cellsImmunological Reviews, 2009
- Mammalian glycosylation in immunityNature Reviews Immunology, 2008
- Protein-glycan interactions in the control of innate and adaptive immune responsesNature Immunology, 2008
- PD-1 and PD-1 ligands: from discovery to clinical applicationInternational Immunology, 2007
- Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte ActivationThe Journal of Experimental Medicine, 2000
- One-Way Stimulation in Mixed Leukocyte CulturesScience, 1966