Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity

Cancer Res. 2020 Jun 1;80(11):2298-2310. doi: 10.1158/0008-5472.CAN-19-3133. Epub 2020 Mar 10.


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 mAbs, 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 mAb 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 antitumor 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. SIGNIFICANCE: These findings demonstrate that glycosylation of PD-1 is functionally significant and targeting glycosylated PD-1 may serve as a means to improve immunotherapy response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents, Immunological / pharmacology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / metabolism
  • Female
  • Glycosylation
  • HEK293 Cells
  • Heterografts
  • Humans
  • Jurkat Cells
  • Leukemia, T-Cell / drug therapy*
  • Leukemia, T-Cell / immunology*
  • Leukemia, T-Cell / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy
  • Nivolumab / pharmacology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • pembrolizumab