Single cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors

PD-1 is an essential inhibitory receptor in T cells, and antibodies that block its interaction with its ligands can augment anti-tumor immune responses. The clinical potential of these agents is limited by the fact that approximately half of all patients who receive anti-PD-1 treatment subsequently develop immune-related Adverse Events (irAEs). To generate insights into the cellular and molecular changes that occur during anti-PD-1 treatment, and to discover predictive biomarkers of irAEs, we performed single cell RNA sequencing of circulating T cells collected from cancer patients who did and did not develop irAEs following PD-1 blockade. Using the K-nearest-neighbor-based network graph drawing layout, we show the involvement of unique gene expression signatures and subpopulations of T cells. We identified that at baseline, patients with arthritis had significantly less cells with features of CD8 TCM cells, patients with pneumonitis had more CD4 TH2 cells, and patients with thyroiditis had more CD4 TH17 cells, when compared to patients who did not develop irAEs. Moreover, T cell receptor sequencing revealed distinctive clonal expansion, and suggested involvement of organ-specific and potentially pathogenic T cell clones among patients with irAEs. Altogether, these data support the hypothesis that different populations of T cells are associated with different irAEs and that quantification and characterization of these populations of T cells pre-treatment could serve as a toxicity-specific, predictive biomarker. T cells were isolated from PBMCs harvested from cancer patients before and after immunoptherapy.