Programmed cell death 1 expression is associated with inferior survival in patients with primary central nervous system lymphoma

Abstract

Programmed cell death 1 (PD-1) and its ligands PD-L1/PD-L2 have been shown to mediate immune evasion in various cancers, but their prognostic implications in patients with primary central nervous system lymphoma (PCNSL) are poorly understood. Therefore, we analyzed 76 PCNSL patients at initial diagnosis who were treated homogenously with high-dose methotrexate-based chemotherapy, and evaluated the prognostic roles of high immunohistochemical PD-1, PD-L1, and PD-L2 expression. The cut-off values for high PD-1 (≥ 70 cells/high power field [HPF]), PD-L1 (≥ 100 cells/HPF), and PD-L2 (≥ 100 cells/HPF) were determined by the area under the receiver operating characteristic curve. Expression of PD-1, PD-L1, and PD-L2 was high in 7.9%, 13.2%, and 42.1% patients, respectively. High PD-1, (P = 0.007) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic scoring (P = 0.019) were independently associated with inferior overall survival on multivariate analysis. High PD-1 also remained an independent prognostic factor for inferior progression-free survival (P = 0.028), as did MSKCC prognostic scoring (P = 0.041) on multivariate analysis. However, there were no differences in survival according to the expression levels of PD-L1/PD-L2 in PCNSL tumor microenvironment. Our results suggest that PD-1 may be considered a biomarker and potential therapeutic target in PCNSL.

Keywords: primary central nervous system lymphoma; prognosis; programmed cell death 1; programmed cell death-ligand 1; programmed cell death-ligand 2.

Figure 1. Representative immunohistochemical stains in formalin-fixed and paraffin-embedded samples

Negative control (a), high PD-1 expression (b), PD-L1 (c), and PD-L2 (d) with anti-PD-1 antibody (NAT105, a and b), anti-PD-L1 antibody (ab58810, c), and anti-PD-L2 antibody (MIH18, d). Magnification, ×400.

Figure 2

The overall survival (OS) and progression-free survival (PFS) according to the level of PD-1 expression (a for OS and b for PFS), PD-L1 expression (c for OS and d for PFS), and PD-L2 expression (e for OS and f for PFS).

Figure 3

The overall survival (OS, a) and progression-free survival (PFS, b) according to the level of PD-1 expression among subgroup of patients who did not receive upfront autologous stem-cell transplantation (ASCT).