PD-1-induced proliferating T cells exhibit a distinct transcriptional signature

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells.
• PD-1 signaling typically inhibits T cell functions, but can also activate certain cellular processes.
• Understanding T cell responses to PD-1 ligation is crucial for optimizing cancer immunotherapy.

Purpose of the Study:

• To investigate the transcriptional and functional differences between proliferating and non-proliferating T cells following PD-1 ligation.
• To explore the potential association of highly proliferating T cells with unresponsiveness to PD-1 blockade therapy.
• To identify T cell subsets that may predict favorable responses to PD-1 blockade treatments.

Main Methods:

• RNA sequencing was performed on T cells stimulated via T-cell receptor and PD-1.
• Transcriptional signatures of proliferating and non-proliferating T cell populations were analyzed.
• Gene expression of follicular helper T cell markers (CXCR5, CCR7, TCF7, BCL6, PRDM1) was assessed at the transcript and protein levels.

Main Results:

• PD-1 ligation resulted in distinct transcriptional profiles for proliferating and non-proliferating T cells.
• Proliferating T cells exhibited enrichment of genes associated with an activated state despite PD-1 signaling.
• Non-proliferating T cells showed enrichment of genes related to circulating follicular helper T cells (cTfh).
• A higher prevalence of cTfh cells was observed in patients responding favorably to PD-1 blockade therapy.

Conclusions:

• Distinct T cell populations with unique transcriptional and functional characteristics emerge upon PD-1 ligation.
• The presence of highly proliferating T cells may contribute to unresponsiveness in PD-1 blockade therapy.
• Increased follicular helper T cells correlate with positive clinical outcomes in patients receiving PD-1 blockade, offering insights into treatment variability.