PD-L1 up-regulation in prostate and oral carcinoma cells

Objectives: Chronic inflammation may contribute to several human malignancies. Porphyromonas gingivalis (P. gingivalis), a keystone Gram-negative oral periodontopathogen, is associated with severe periodontitis. It expresses a variety of virulence factors to invade into host cells and alter immune response. In this study expression and signaling pathways of the programmed death-ligand 1 (PD-L1) in a prostate cancer cell and an oral squamous carcinoma cell line were studied. The aim of this study was to reveal the mechanisms of infection-induced immune evasion of human carcinomas.

Methods: The prostate cancer cell line DU-145 and the oral squamous carcinoma cell line SCC-25 were stimulated with the P. gingivalis membrane fraction. Chemical inhibitors were used to block different components of mitogen-associated protein kinase (MAPK) and nuclear factor (NF)-κB signaling to investigate the pathway involved in PD-L1 expression. Detection of PD-L1 expression was analyzed using Western blots 24h after stimulation.
Results: PD-L1 expression increased significantly (p < 0.05) in both cell lines upon P. gingivalis infection. Up-regulation of PD-L1 could be blocked effectively using gefitinib, an inhibitor of the receptor-interacting serine/threonine-protein kinase 2 (RIP2), a component of the signaling cascades of innate and adaptive immune response which is recruited by nucleotide-binding oligomerization domain-containing proteins (NOD)1 and NOD2. Gefitinib (10 µM) reduced PD-L1 expression by 62.7±31% in DU-145 and 75.1± 23% in SCC-25 cells. All experiments were performed in triplicate.

Conclusions: Increase of PD-L1 expression in prostate cancer cells and oral squamous carcinoma cells involves the pathway, which is regulated by essential components of the NOD1 and NOD2 signaling cascade. Chronic inflammation may contribute to tumor immune-evasion by modulating the tumor microenvironment. Chronic infections, like periodontitis, possibly play an important role in the development and progression of human carcinomas.
Acknowledgements: This study was supported by a grant of the Von-Behring-Röntgen-Stiftung.