Abstract
BackgroundThe 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.MethodsSixty-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.ResultsThe 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).ConclusionsSerum 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 registrationThe 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]).
Highlights
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 Programmed death-1 ligand (PD-L1) from progressive disease (PD)-L1 expressing tumor cells
Response was assessed according to the response criteria for primary central nervous system lymphoma (PCNSL) recommended by the International Primary CNS Lymphoma Collaborative Group [21]: complete response (CR) was defined as no contrast enhancement in brain magnetic resolution imaging (MRI) and negative findings in ocular and Cerebrospinal fluid (CSF) examinations; partial response (PR) was defined as at least a 50% decrease in the enhancing tumor lesion; progressive disease (PD) was defined as at least a 25% increase in the lesion or any new lesion in the CNS or systemic sites; and stable disease (SD) was defined as less than a PR but not PD
The low level of soluble PD-L1 (sPD-L1) in PCNSL might be associated with the peculiar characteristics of PCNSL: tumors confined to the CNS have relatively small volume, and the blood-brain barrier might influence the level of sPD-L1 circulating in blood
Summary
Sixty-eight patients with newly diagnosed PCNSL had diffuse large B-cell lymphoma and were treated with high-dose methotrexate-containing chemotherapy. Treatment and outcome-related data, including treatment regimens, tumor response, date of progression, and date of death, were regularly updated These cohort studies were approved by the Institutional Review Board of Samsung Medical Center, and all investigations were conducted according to the principles expressed in the Declaration of Helsinki and its contemporary amendments. Response was assessed according to the response criteria for PCNSL recommended by the International Primary CNS Lymphoma Collaborative Group [21]: complete response (CR) was defined as no contrast enhancement in brain magnetic resolution imaging (MRI) and negative findings in ocular and CSF examinations; partial response (PR) was defined as at least a 50% decrease in the enhancing tumor lesion; progressive disease (PD) was defined as at least a 25% increase in the lesion or any new lesion in the CNS or systemic sites; and stable disease (SD) was defined as less than a PR but not PD. Response evaluation was performed after the completion of primary treatment chemotherapy, and surveillance brain MRI was done to monitor the occurrence of disease relapse
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