Low PD-L1 Expression Strongly Correlates with Local Recurrence in Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma after Radiation-Based Therapy

Abstract

The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs (p = 0.0012), TCs (p = 0.013) or both (p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor (p = 0.0080; HR = 1.88; 95% CI = 1.18⁻3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor (p = 0.022; HR = 0.46; 95% CI = 0.24⁻0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials.

Keywords: Epstein-Barr virus; immunohistochemistry; local recurrence; nasopharyngeal carcinoma; programmed death-ligand 1; radiotherapy; survival.

Figure 1

The local recurrence rates in patients with different levels of programmed death-ligand 1 (PD-L1) expression on immune cells (ICs) and tumor cells (TCs).

Figure 2

Local recurrence-free survival (LRFS) in patients with different levels of PD-L1 expression on immune cells (ICs) and tumor cells (TCs). There was significantly shorter LRFS in patients with low PD-L1 expression on ICs (a), TCs (b), or both ICs and TCs (c). Significantly longer LRFS was observed in patients with high PD-L1 expression on both ICs and TCs (d).

Figure 3

Distant metastasis-free survival (DMFS) in patients with different levels of PD-L1 expression on immune cells (ICs) and tumor cells (TCs). PD-L1 expression on ICs (a), TCs (b), or both ICs and TCs (c,d) had no significant influence on DMFS.

Figure 4

Disease-free survival (DFS) in patients with different levels of PD-L1 expression on immune cells (ICs) and tumor cells (TCs). Low PD-L1 expression on ICs (a) or both ICs and TCs (c) was associated with shorter DFS. PD-L1 expression on TCs (b) had no significant influence on DFS. High PD-L1 expression on both ICs and TCs (d) correlated with longer DFS.

Figure 5

Overall survival (OS) in patients with different levels of PD-L1 expression on immune cells (ICs) and tumor cells (TCs). Low PD-L1 expression on ICs (a), TCs (b), or both ICs and TCs (c) had no significant influence on OS. High PD-L1 expression on both ICs and TCs (d) correlated with significantly longer OS.

Figure 6

Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) is characterized by poorly differentiated tumor cells (TCs) and many admixed immune cells (ICs) (a; H&E stain). Nuclear EBV-encoded small RNAs (EBER) signal is present in the TCs (b; in situ hybridization). Also seen are examples of cases with PD-L1-low on both TCs and ICs (c), PD-L1-high on TCs and PD-L1-low on ICs (d), PD-L1-low on TCs and PD-L1-high on ICs (e), and PD-L1-high on both TCs and ICs (f). Note that TCs have much larger nuclei than the ICs have. The original magnification of all microscopic images was × 400.