Serum levels of soluble programmed death-ligand 1 (sPD-L1) in patients with primary central nervous system diffuse large B-cell lymphoma

Inju Cho, Hansang Lee, Sang Eun Yoon, Kyung Ju Ryu, Young Hyeh Ko, Won Seog Kim, Seok Jin Kim, Inju Cho, Hansang Lee, Sang Eun Yoon, Kyung Ju Ryu, Young Hyeh Ko, Won Seog Kim, Seok Jin Kim

Abstract

Background: The interaction of programmed death-1 protein (PD-1) and programmed death-1 ligand (PD-L1) produces immunosuppressive activity, protecting tumor cells from anti-tumor immunity and possibly releasing soluble PD-L1 (sPD-L1) from PD-L1 expressing tumor cells. Therefore, we measured serum levels of sPD-L1 in patients with primary central nervous system lymphoma (PCNSL) and explored its clinical implications.

Methods: Sixty-eight patients with newly diagnosed PCNSL had diffuse large B-cell lymphoma and were treated with high-dose methotrexate-containing chemotherapy. The measurement of sPD-L1 and cytokines was performed using serum samples archived at diagnosis, and the tissue expression of PD-L1 was also analyzed from archived paraffin-embedded tissue blocks. Disease relapse, progression-free survival (PFS), and overall survival (OS) were analyzed according to the extent of sPD-L1 in serum and PD-L1 in tissue.

Results: The median level of serum sPD-L1 (0.429 ng/mL) was higher than in healthy control patients (0.364 ng/mL). The occurrence of relapse was more frequent in the high sPD-L1 (78%) than the low sPD-L1 group (50%), though the groups did not have different clinical or pathological characteristics at diagnosis. As a result, the OS and PFS for the high sPD-L1 group were significantly lower than those in the low group. PD-L1-positive tumor cells were found in 35 patients (67%), and the extent of PD-L1-postive tumor cells was positively associated with serum sPD-L1 levels (r = 0.299, P = 0.031). Among the 34 cytokines analyzed, only the serum level of IL-7 correlated with the serum level of sPD-L1 (r = 0.521, P < 0.001).

Conclusions: Serum levels of sPD-L1 could reflect the expression of PD-L1 in PCNSL tumor cells and predict patient survival outcomes. Therefore, sPD-L1 in serum could be a feasible biomarker for determining a risk-adapted treatment strategy for PCNSL patients.

Trial registration: The study population was patients who were diagnosed with PCNSL between January 2009 and February 2017 and registered for our prospective cohort studies after providing written informed consent (ClinicalTrials.gov: NCT00822731 [date of registration - January 14, 2009] and NCT01877109 [date of registration - June 13, 2013]).

Keywords: PD-1; Primary central nervous system lymphoma; Soluble PD-L1.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a Comparison of serum sPD-L1 between patients with PCNSL (n = 68) and the healthy control group (P < 0.01). b The distribution of serum sPD-L1 in 68 patients. c The ROC curve of sPD-L1 for overall survival. d, e The overall survival and progression-free survival in the high sPD-L1 group were lower than those in the low sPD-L1 group
Fig. 2
Fig. 2
a The extent of PD-L1 expression in the first and second quartiles (Q1, Q2) of serum sPD-L1 was lower than that in the third and fourth quartiles (Q3, Q4). b The association between PD-L1-postive tumor cells and serum levels of sPD-L1 (r = 0.299, P = 0.031). c The percentage of PD-L1-postive immune cells did not correlate with serum levels of sPD-L1. d, e Comparison of overall survival based on the percentage of PD-L1-positive tumor cells (< 1% versus ≥1%) and the percentage of PD-L1-positive immune cells (< 3% versus ≥3%)
Fig. 3
Fig. 3
a The association between serum IL-7 levels and serum sPD-L1 levels (r = 0.521, P < 0.001). b The high sPD-L1 group showed a higher level of IL-7 than the low sPD-L1 group. c Comparison of overall survival based on the median value of Il-7 showed a trend of worse OS for patients in the high IL-7 group compared with those in the low IL- group

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