Abstract
The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival. As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.
Highlights
Esophageal cancer is one of the most common types of human cancer and a difficult gastrointestinal tumor to treat and cure [1]
The Immunohistochemical staining (IHC) data for tissue microarray (TMA) slides demonstrated that programmed cell death 1 ligand 1 (PD-L1) was over-expressed at the membrane or in the cytoplasm of tumor cells in the surgically resected tumor specimens compared to adjacent nonmalignant epithelial tissues (Figure 1a)
Given the positive association between IL-6 and PD-L1 expression in esophageal squamous cell carcinoma (ESCC) tumors, we examined the expression of PD-L1 in esophageal cancer cell lines whose IL-6 was regulated
Summary
Esophageal cancer is one of the most common types of human cancer and a difficult gastrointestinal tumor to treat and cure [1]. Most patients who undergo curative treatment for esophageal cancer will eventually relapse and die as a result of their disease. Identification of the potential molecular markers for predicting the treatment response and understanding the molecular mechanisms underlying is important for the effective management and improving prognosis of esophageal cancer. Tumor-induced immune suppression in cancer patients is a major issue that promotes tumor progression and inhibits the efficiency of anti-cancer treatment [4, 5]. One of the major molecular regulators of tumor immune escape is programmed cell death 1 ligand 1 (PD-L1). The issue to explore the key targets that can block PD-L1 expression and enhance T-cell function in cancers has been brought into spotlight
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