Programmed cell death 1 expression and Epstein-Barr virus infection in chronic lymphocytic leukaemia: a prospective cohort study

Purpose: Infection with Epstein-Bar virus (EBV) is associated with an unfavourable prognosis in chronic lymphocytic leukaemia (CLL), but the underlying mechanisms remain unknown. We aimed to establish whether EBV worsens the course of CLL by up-regulating the programmed cell death 1 expression. Patients and methods: Using polymerase chain reaction, we measured EBV DNA in the blood of 110 newly diagnosed, treatment-naive patients with CLL. We used flow cytometry to measure the expression of programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand (PD-L1) on CD4+, CD8+, and CD19+ cells. Additionally, PD-1 and PD-L1 serum concentrations were measured using enzyme-linked immunosorbent assays. We related the expressions of PD-1 and PD-L1 to EBV DNA load and clinical outcomes. Results: Fifty-nine (54%) patients had detectable EBV DNA [EBV(+)], and these patients had more advanced disease at baseline than the rest. PD-1 and PD-L1 serum concentrations and their expressions on all cell populations were higher in EBV(+) than EBV(-) patients. EBV load correlated positively with unfavourable clinical markers of CLL and the expression of PD-1 and PD-L1 on CD4+ and CD8+ cells (rho =0.42-0.75; p<0.001). EBV(+) patients had increased risks of treatment initiation and lymphocyte doubling during a median follow-up period of 32 months (p<0.001). Among EBV(+), but not EBV(-), patients, higher expressions of PD-1 and PD-L1 on CD4+ and CD8+ cells were associated with higher risks of treatment initiation and lymphocyte doubling (p <= 0.020). Conclusion: EBV-induced up-regulation of PD-1-PD-L1 expression is associated with worse outcomes in CLL.