Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory function in human T cells

Area of Science:

• Immunology
• Cancer Research
• Molecular Biology

Background:

• Programmed cell death protein 1 (PD-1) is a key target in cancer immunotherapy, but its effectiveness is limited to a subset of patients.
• Identifying patients whose T cells exhibit PD-1-mediated inhibition is crucial for optimizing PD-1-blocking therapy success.

Purpose of the Study:

• To develop a novel method for detecting PD-1-mediated inhibitory signaling in T cells.
• To establish a potential biomarker for patient selection in PD-1-targeted cancer immunotherapy.

Main Methods:

• Generated a specific antibody targeting phosphorylated PD-1 at tyrosine 248 (pPD-1 Y248).
• Examined pPD-1 expression in human T cells following stimulation and PD-1 ligation.
• Analyzed pPD-1 expression in peripheral blood, tumor-draining lymph nodes of mice, and glioblastoma patient biopsies.

Main Results:

• Phosphorylated PD-1 (pPD-1) expression was upregulated by T cell receptor (TCR)/CD3 + CD28 stimulation and concurrent PD-1 ligation.
• PD-1 pY248-positive (pPD-1+) CD8+ T cells were identified in human peripheral blood and demonstrated impaired effector function.
• pPD-1+ T cells were also detected in tumor-bearing mice and glioblastoma patient samples.

Conclusions:

• The detection of pPD-1+ T cells can serve as a reliable biomarker.
• This biomarker aids in identifying T cells undergoing PD-1-mediated immunosuppression.
• This approach may improve patient stratification for PD-1-blocking therapies.