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Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint
Shoiab Bukhari1, Brian S Henick2, Robert J Winchester3
1Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Abstract:
PD-1 is an inhibitory receptor in T cells, and antibodies that block its interaction with ligands augment anti-tumor immune responses. The clinical potential of these agents is limited by the fact that half of all patients develop immune-related adverse events (irAEs). To generate insights into the cellular changes that occur during anti-PD-1 treatment, we performed single-cell RNA sequencing of circulating T cells collected from patients with cancer. Using the K-nearest-neighbor-based network graph-drawing layout, we show the involvement of distinctive genes and subpopulations of T cells. We identify that at baseline, patients with arthritis have fewer CD8 TCM cells, patients with pneumonitis have more CD4 TH2 cells, and patients with thyroiditis have more CD4 TH17 cells when compared with patients who do not develop irAEs. These data support the hypothesis that different populations of T cells are associated with different irAEs and that characterization of these cells' pre-treatment has the potential to serve as a toxicity-specific predictive biomarker.
Insights
Anti-PD-1 cancer therapy can cause immune-related adverse events (irAEs). Pre-treatment T-cell populations, like CD8 Tcm and CD4 Th2/Th17 cells, may predict specific irAEs, aiding toxicity management.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Programmed cell death protein 1 (PD-1) inhibitors enhance anti-tumor immunity but can cause immune-related adverse events (irAEs).
- Understanding the T-cell dynamics during anti-PD-1 therapy is crucial for managing irAEs.
Purpose of the Study:
- To investigate T-cell subpopulations and gene expression profiles associated with irAEs during anti-PD-1 treatment.
- To identify potential predictive biomarkers for specific irAEs.
Main Methods:
- Single-cell RNA sequencing of circulating T-cells from cancer patients undergoing anti-PD-1 therapy.
- K-nearest-neighbor-based network graph analysis to identify T-cell subpopulations and gene involvement.
Main Results:
- Distinct T-cell subpopulations and gene expression patterns were identified in patients who developed irAEs.
- Patients with arthritis showed fewer CD8 Tcm cells; those with pneumonitis had more CD4 Th2 cells; and those with thyroiditis had more CD4 Th17 cells at baseline compared to controls.
- These findings suggest a link between specific T-cell populations and distinct irAEs.
Conclusions:
- Pre-treatment characterization of T-cell populations may serve as a toxicity-specific predictive biomarker for anti-PD-1 therapy.
- Identifying patients at risk for specific irAEs can guide personalized treatment strategies and improve patient outcomes.
