Programmed cell death 1 expression and Epstein-Barr virus infection in chronic lymphocytic leukaemia: a prospective cohort study
Authors Grywalska E, Pasiarski M, Sosnowska-Pasiarska B, Macek P, Rolińska A, Samardakiewicz M, Ludian J, Góźdź S, Roliński J
Received 13 April 2019
Accepted for publication 4 July 2019
Published 12 August 2019 Volume 2019:11 Pages 7605—7618
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 2
Editor who approved publication: Dr Eileen O'Reilly
Ewelina Grywalska,1 Marcin Pasiarski,2,3 Barbara Sosnowska-Pasiarska,4 Paweł Macek,5 Agnieszka Rolińska,6 Marzena Samardakiewicz,6 Jarosław Ludian,1 Stanisław Góźdź,3,7 Jacek Roliński1
1Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Lublin, Poland; 2Department of Hematology, Holy Cross Oncology Center of Kielce, Kielce, Poland; 3Faculty of Health Sciences, Jan Kochanowski University, Kielce, Poland; 4Department of Oncocardiology, Holy Cross Oncology Center of Kielce, Kielce, Poland; 5Department of Cancer Epidemiology and Cancer Control, Holy Cross Oncology Center of Kielce, Kielce, Poland; 6Department of Applied Psychology, Medical University of Lublin, Lublin, Poland; 7Department of Oncology, Holy Cross Oncology Center of Kielce, Kielce, Poland
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-naïve 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.
Keywords: chronic lymphocytic leukaemia, Epstein-Barr virus, programmed cell death protein 1, programmed cell death protein 1 ligand
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