Tumor-Intrinsic PD-L1 Exerts an Oncogenic Function through the Activation of the Wnt/beta-Catenin Pathway in Human Non-Small Cell Lung Cancer

Programmed death ligand 1 (PD-L1) strongly inhibits T cell activation, thereby aiding tumors in escaping the immune response. PD-L1 inhibitors have proven to be effective in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). Yet, the knowledge regarding the biological function of tumor-intrinsic PD-L1 in lung cancer remains obscure. In our study, we set the goal of determining the function of PD-L1 using overexpression and knockdown strategies. PD-L1 silencing resulted in decreased migratory and invasive ability of tumor cells, together with attenuated colony-forming capacity. Ectopic expression of PD-L1 showed the opposite effects, along with increased activities of MAPK and Wnt/beta-catenin pathways, and the upregulation of Wnt/beta-catenin target genes. Additionally, overexpression of PD-L1 was associated with dysregulated cellular and exosomal miRNAs involved in tumor progression and metastasis. In primary lung tumors, immunohistochemistry revealed that both PD1 and PD-L1 were highly expressed in squamous cell carcinoma (SCC) compared to adenocarcinoma (p=0.045 and p=0.036, respectively). In SCC, PD1 expression was significantly associated with tumor grading (p=0.016). Taken together, our data suggest that PD-L1 may exert an oncogenic function in NSCLC through activating Wnt/beta-catenin signaling, and may act as a potential diagnostic marker for lung SCC.

Automated summary

PD-L1 may play an oncogenic role in non-small cell lung cancer (NSCLC) by activating the Wnt/β-catenin signaling pathway and may act as a potential diagnostic marker for squamous cell carcinoma (SCC) of the lung.