Abstract
BackgroundThe programmed cell death ligand 1 (PD-L1) plays a key role in glioma development. However, due to the specificity of glioma’s anatomical position, the role of its expression as a tumor biomarker is limited. It has been proven that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in many malignancies including glioma. However, the expression of sPD-L1 in glioma patients receiving radiotherapy (RT) remains unclear. The purpose of this study was to evaluate the concentration of sPD-L1 in the plasma of glioma patients before and after RT and to explore its relationship with clinical outcomes.MethodsBetween October 2017 and September 2018, glioma patients treated with RT (30 ± 10 Gy, 2 Gy/f) were enrolled, and blood samples were collected before and after RT. We quantified the sPD-L1 levels by enzyme-linked immunosorbent assay (ELISA). The isocitrate dehydrogenase-1 (IDH-1) mutational status and Ki-67 expression of tumors were evaluated by immunohistochemistry. Glioma murine model were used to address whether circulating sPD-L1 molecules are directly targeted by an anti-PD-L1 antibody. The associations between sPD-L1 and clinical features were assessed with Pearson’s or Spearman’s correlation analysis. The progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan-Meier method.ResultsSixty glioma patients were included, with a median age of 52 years. The proportions of grade I, II, III, and IV gliomas were 6.7%, 23.3%, 28.4%, and 41.6%, respectively. The baseline sPD-L1 levels were significantly associated with tumor grade, IDH-1 mutation status and Ki-67 expression. Using 14.35 pg/ml as the cutoff, significantly worse PFS and OS were both observed in patients with higher baseline levels of sPD-L1 (P = 0.027 and 0.008, respectively). RT significantly increased the mean level of sPD-L1 (P < 0.001). Further analysis showed that the level of sPD-L1 in IDH-1 mutation patients was higher than that in wild-type patients. Furthermore, an analysis of glioma murine model indicated that anti-PD-L1 antibody combine with RT can be a potentially powerful cancer therapy.ConclusionThis study reported that sPD-L1 might be a potential biomarker to predict the outcome in glioma patients receiving RT. The elevated level of sPD-L1 after RT suggested that the strategy of a combination of immune checkpoint inhibitors and RT might be promising for glioma patients, especially for those with IDH-1 mutations.
Highlights
Gliomas are the most common primary brain tumors, with a 5year overall survival (OS) of approximately 36% [1]
To address whether circulating soluble programmed death-ligand 1 (sPD-L1) molecules are directly targeted by an anti-programmed cell death ligand 1 (PD-L1) antibody, we performed in vivo studies using the glioma murine model treated with IR (20 Gy), anti-PD-L1 or IR plus anti-PD-L1; we found that there was no difference in baseline sPD-L1 expression levels among the different groups (1.58 ± 0.315 pg/ml, 1.69 ± 0.24 pg/ml, and 1.18 ± 0.51 pg/ml, respectively, P = 0.227; Figures 5A, B)
This study reported that sPD-L1 can be assayed in the plasma of glioma patients
Summary
Gliomas are the most common primary brain tumors, with a 5year overall survival (OS) of approximately 36% [1]. One phase III clinical trial, Checkmate 143, has been completed; nivolumab did not exhibit increased survival benefits compared with bevacizumab [9]. It seems that the PD-1/PD-L1 axis only plays one role in the malignant biological behavior of gliomas, while other molecular signaling networks may play indispensable roles. Researchers tried to explore the clinical efficacy of immunotherapy (nivolumab) + radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma patients in some ongoing phase III clinical trials, including Checkmate 498 (NCT02617589) and Checkmate 548 (NCT02667587). The purpose of this study was to evaluate the concentration of sPD-L1 in the plasma of glioma patients before and after RT and to explore its relationship with clinical outcomes
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