EV PD-L1 is Correlated With Clinical Features and Contributes to T Cell Suppression in Pediatric Thyroid Cancer

Context: The contribution of blood extracellular vesicular (EV) programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) in papillary thyroid cancer (PTC) is uncertain. Objective: We sought to determine the relationship of EV PD-L1/PD-1 with the clinical features of pediatric PTC and the role of EV PD-L1 in immunosuppression. Main Outcome Measures: Plasma levels of EV and soluble PD-L1 and PD-1 and levels of plasma cytokines in children with PTC and controls were determined by enzyme-linked immunosorbent assay. Levels of tumor PD-L1 and the tumor-infiltrating lymphocyte (TIL) score were determined by immunohistochemistry. Correlations of the plasma PD-L1/PD-1 level with clinicopathological characteristics, levels of plasma cytokines, tumor PD-L1 expression, and TIL score were analyzed. T-cell suppression by EVs from PTC patients was determined by incubation of PD-L1(high) or PD-L1(low) EVs with activated CD8(+) T cells. Changes in CD69 and PD-1 expression and changes in tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) secretion were measured by flow cytometry. Results: The levels of plasma PD-L1/PD-1 were significantly higher in children with PTC than in controls. The levels of plasma EV PD-L1 significantly correlated with tumor T stage, tumor PD-L1 expression, TIL score, and plasma cytokine content. Levels of plasma soluble PD-1 significantly correlated with patient age, plasma EV PD-L1, and IFN alpha concentration. PD-L1(high) EVs significantly inhibited the activation of CD8(+) T cells. Conclusions: Plasma levels of EV PD-L1, but not soluble PD-L1, were associated with tumor T stage in children with PTC. Plasma EV PD-L1 emerges as a useful metric for assessing tumor T stage and T cell suppression in PTC.