Background: Enhancer of zeste homolog 2 (EZH2) is reported to be involved in lung cancer pathogenesis via the epigenetic regulation of various genes. Recently, EZH2 was shown to control mechanisms of adaptive resistance to immunotherapy in melanoma; however, the association between EZH2 and programmed death-ligand 1 (PD-L1), which reflects the tumor microenvironment, remains poorly understood. Methods: A total of 428 patients with resected lung adenocarcinoma were analyzed for their EZH2 and PD-L1 expression by immunohistochemistry and evaluated to determine the association between the EZH2 and PD-L1 expression. Results: Among 428 patients, the EZH2 expression was identified in 219 (51.2%) patients, while the PD-L1 expression was observed in 88 (20.6%) patients. The recurrence-free and overall survival were significantly shorter in patients with the EZH2 expression than in those without it. A multivariate analysis showed that EZH2 remained an independent prognosticator for recurrence-free and overall survival. Patients with the EZH2-positive lung adenocarcinoma exhibited a significantly higher expression of PD-L1 than did those without it. A logistic regression analysis with backward elimination revealed that the presence of lymphatic and vessel invasion and PD-L1 positivity were independently associated with the EZH2 expression, while age over 70 years, the presence of vessel invasion, wild-type epidermal growth factor receptor, and EZH2 positivity were significantly associated with the PD-L1 expression. Conclusions: EZH2-expressing lung adenocarcinomas were shown to express the PD-L1 protein more frequently than were nonexpressing lesions. This study provides the first evidence of a possible association between the EZH2 and PD-L1 expression in patients with resected lung adenocarcinoma.
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