Abstract 5187: Effect of histone deacetylase inhibitor on PD-L1 expression in lung cancer cells
Authors: Umamaheswari Natarajan, Thiagarajan Venkatesan, R Vijayaraghavan, Shila Samuel, Appu Rathinavelu
Journal: Cancer Research (2019)

Abstract Programmed Cell Death Ligand-1 (PD-L1) is frequently expressed on tumor cells and tumor-infiltrating immune cells. The expression of PD-L1 is indicative of immunosuppression and cause for poor prognosis in several cancers. The effects of PD-L1 are mediated through its binding to the Programmed Cell Death-1 (PD-1) receptor, which is a co-inhibitory surface molecule that is expressed on lymphoid and non-lymphoid derived cells. After PD-L1 binding the PD-1 receptor mediates the signals intracellularly to suppress peripheral T-cell responses. Therefore, determining the mechanisms of up-regulation or down-regulation of the PD-L1 is very crucial for the purpose of devising strategies to reactivate the T-cells that can lead to enhanced tumor attack. However, the cellular mechanisms that determine the levels of PD-L1 are not fully understood at this time. Hence, we analyzed different cancer cell lines for the expression levels of PD-L1 and confirmed the highest-level of expression in HCC827 lung cancer cells. In addition, H460, H1975 (Lung Cancer), SJSA1 (Osteosarcoma) and U-87 MG (Glioblastoma) cells were found to express PD-L1 in high levels. Relatively, lower level expression of PD-L1 was detected in H226 (Squamous Cell Carcinoma) PANC-1 (Pancreatic Cancer), CFPAC-1 (Pancreatic, Ductal Adenocarcinoma) and LNCaP (Prostate Cancer) cells compared to HCC827. Since, alterations in gene expressions are often regulated by epigenetic modifications, we conducted experiments to determine whether the expression of PD-L1 can also be altered by the HDAC inhibitor SAHA (Suberoylanilide hydroxamic acid). In our experiments, SAHA (7.5 μM) was able to reduce the expression of PD-L1 in a time and dose dependent manner and produced more than 50% decrease in the protein levels within 24 hrs. while the level of PD-L1 was significantly reduced, concomitant decreases in EGFR, phospho-EGFR levels were also observed in HCC827 cells following SAHA treatment. Furthermore, SAHA was able to increase the levels of acetyl-H2B, acetyl-H3 and acetyl-H4, which confirmed the impact of HDAC inhibition on the acetylation status of histones. Since de-acetylation mediated unwinding of the DNA is typically responsible for the increased expression of genes such as p21/CDKN1A, it is suspected that the decrease in the PD-L1 levels may be due to reduced transcription of the CD274 gene that is coding for PD-L1. However, it is not clear whether the decrease in PD-L1 expression observed is because of p21 mediated negative control on the transcription process or due to some other mechanism. Additional studies are required to fully understand the actual mechanisms that may be involved in the regulation of PD-L1 expression by HDACs and their inhibitors. (This research was supported by the Royal Dames of Cancer Research Inc., Fort Lauderdale, Florida). Citation Format: Umamaheswari Natarajan, Thiagarajan Venkatesan, R Vijayaraghavan, Shila Samuel, Appu Rathinavelu. Effect of histone deacetylase inhibitor on PD-L1 expression in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5187.