Programmed death ligand 1 expression in esophageal cancer following definitive chemoradiotherapy: Prognostic significance and association with inflammatory biomarkers

Abstract

Immunotherapy with anti-programmed cell death protein 1 or programmed death ligand 1 (PD-L1) agents has demonstrated promising efficacy for the treatment of various types of malignancies. However, the role of PD-L1 as a tumor prognostic marker remains poorly understood. In the present study, the prognostic value of PD-L1 expression in esophageal carcinoma (EC) following definitive chemoradiotherapy (CRT) was investigated, and its associations with three systemic inflammation biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) were further explored. A total of 104 patients with non-metastatic EC, who underwent definitive CRT between January 2009 and December 2012, were retrospectively analyzed. The expression of PD-L1 was examined by immunohistochemistry and the impact of PD-L1 expression level on overall survival (OS) was assessed. Furthermore, pretreatment neutrophil, lymphocyte, platelet and monocyte counts were obtained from routine blood tests to calculate the NLR, PLR and LMR. PD-L1 was overexpressed in EC compared with normal esophageal epithelium, with a positive expression rate of 37.5%. Additionally, patients with positive PD-L1 expression had a lower NLR than those with negative PD-L1 expression (P=0.001). On multivariate analysis, the positive staining of PD-L1 was significantly associated with improved OS (HR, 0.6; 95% CI, 0.372-0.965; P=0.035). Kaplan-Meier survival analysis showed a similar result (P=0.009). Additionally, sex (HR, 0.449; 95% CI, 0.229-0.880; P=0.020), clinical stage III (HR, 2.471; 95% CI, 1.171-5.212; P=0.018), and receipt of concurrent chemoradiation (HR, 0.590; 95% CI, 0.368-0.945; P=0.028) were all independent prognostic factors in EC treated with definitive CRT. The correlation of NLR with PD-L1 expression validated the relevance of immunity and inflammation. In summary, the present study demonstrated that positive PD-L1 expression is associated with improved survival in patients with EC treated with radical CRT, indicating that PD-L1 is a promising prognostic marker.

Keywords: esophageal cancer; lymphocyte-monocyte ratio; neutrophil-lymphocyte ratio; platelet-lymphocyte ratio; prognostic factors; programmed death ligand 1.

Figure 1.

PD-L1 expression in EC and normal esophageal epithelium. (A) No PD-L1 staining in normal esophageal epithelium (magnification, ×200). (B) Negative expression of PD-L1 in EC (magnification, ×200). (C) Positive expression of PD-L1 in the cytoplasm and membrane of EC cells (magnification, ×100). (D) Positive expression of PD-L1 in the cytoplasm and membrane of EC cells (magnification, ×200). PD-L1, programmed death ligand 1; EC, esophageal carcinoma.

Figure 2.

Correlation between PD-L1 and NLR, LMR and PLR. The two groups, divided according to the positive or negative expression of PD-L1, exhibited differences in NLR values (P=0.001, Student's t-test), whereas PLR and LMR did not differ significantly between the groups (P=0.448 and P=0.056, respectively). PD-L1, programmed death ligand 1; NLR, neutrophil-lymphocyte ratio; PLR, platelet-lymphocyte ratio; LMR; lymphocyte-monocyte ratio.

Figure 3.

Kaplan-Meier curves showing differences in overall survival rates according to (A) sex, (B) clinical stage, (C) receipt of concurrent chemoradiation, and (D) PD-L1 expression in patients with esophageal carcinoma. P-values were determined by log-rank test. PD-L1, programmed death ligand 1.