PD-L1 Expression and Its Regulation in Lung Adenocarcinoma with ALK Translocation.

Background: The mechanism of regulation of PD-L1 expression by ALK translocation remains unclear. We detected PD-L1 protein expression and its regulation in lung adenocarcinoma patients with EML4-ALK fusion gene.

Methods: PD-L1 and ALK expression at protein level in human lung adenocarcinoma cell lines and tumor tissue specimens was evaluated by immunohistochemistry analysis and Western blotting. The expression at DNA level and RNA level was indicated by quantitative real-time PCR analysis. The signal pathway was indicated at protein level by western blotting.

Results: The PD-L1 protein expression was higher in human lung adenocarcinoma cell lines with EML4-ALK fusion gene than that without this fusion gene. Induced expression of EML4-ALK in A549 cells significantly increased PD-L1 protein expression, whereas PD-L1 protein expression was downregulated after crizotinib and pembrolizumab successively. Significant positive correlations between PD-L1 and p-ERK, p-STAT3 or p-AKT expression were observed in ALK-translocated tumors. PD-L1 overexpression was significantly associated with shorter progressive survival and overall survival after crizotinib in ALK-translocated patients.

Conclusions: We demonstrate that ALK translocation can upregulate PD-L1 expression by activating ERK, STAT3 and AKT pathways. ALK inhibitor combined with a PD-L1-targeted therapy may be a potential strategy in ALK-translocated lung adenocarcinoma patients.