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Abstract
Programmed death-ligand 1 (PD-L1) plays an essential protein for immune evasion, contributing to tumor development and progression. Recent studies have reported MET as an upregulator for PD-L1 overexpression through an oncogenic pathway. However, an association between PD-L1 expression with MET has not been reported in gastric cancer.The prognostic significance of PD-L1 and its association with Epstein-Barr virus (EBV), microsatellite instability (MSI), and mucin phenotype remain controversial.We performed in situ hybridization for EBV-encoded RNA and immunohistochemistry in tissue microarrays for 394 gastric cancers. A multiplex polymerase chain reaction with five quasimonomorphic markers was performed for MSI.PD-L1 expression was observed in 123 cases (31.2%), and clinicopathological features such as MET overexpression, high pT stage, and a lack of lymphatic invasion represent significant risk factors associated with PD-L1 overexpression in gastric cancers. No associations of EBV, MSI, or mucin phenotype with PD-L1 expression were statistically significant. PD-L1 expression was a strong indicator for worse overall survival (OS) but borderline significant in disease-free survival (DFS). A combined analysis of PD-L1 and MET expression indicated that the PD-L1+/MET+ subgroup showed the worst prognosis when compared to the PD-L1-/MET- subgroup, which had the best clinical outcome. Furthermore, PD-L1 overexpression exhibited poor prognosis in terms of both OS and DFS in EBV-negative, microsatellite stable, and intestinal mucin phenotype tumors. In conclusion, this is the first study to evaluate the overexpression of MET as a risk factor for PD-L1 positivity in gastric cancer tissue as well as the reliability and prognostic relevance of PD-L1/MET co-expression after surgery.
Highlights
Gastric cancer is the fourth most common human malignancy and the second leading cause of global cancer mortality, and is notorious for a dismal prognosis with a five-year survival rate of less than 40% despite multimodality treatments [1]
Binding of hepatocyte growth factor (HGF) to MET induces the phosphorylation of the docking site and stimulates mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways [13], which are one of the drivers that upregulate programmed death-ligand 1 (PD-L1) expression in melanoma and non-small cell lung cancer [6, 14]
This study demonstrated that PD-L1 expression, comprising one third of gastric cancers, could be a strong prognostic indicator in patients with gastric cancer
Summary
Gastric cancer is the fourth most common human malignancy and the second leading cause of global cancer mortality, and is notorious for a dismal prognosis with a five-year survival rate of less than 40% despite multimodality treatments [1]. A proportion of PD-L1-negative patients benefits from anti-PD-1 therapy This suggests that PD-L1 expression per se has not been fully accounted for its survival benefit, and there may be other molecular determinants involved in PD-L1 expression and its therapeutic effects. Binding of HGF to MET induces the phosphorylation of the docking site and stimulates mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways [13], which are one of the drivers that upregulate PD-L1 expression in melanoma and non-small cell lung cancer [6, 14]. A correlation between PD-L1 expression with EBV, MSI, or mucin phenotype has not been fully evaluated in Korean patients with gastric cancer. We focused on the aberrant co-overexpression of PD-L1 and MET in gastric cancers to determine whether this aberrant expression was associated with the clinical outcome. Since gastric cancers are therapy-resistant and they have few established prognostic and predictive markers, studies on PD-L1 and its related oncogenic pathway in gastric cancers may provide insight into novel treatment modalities
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