Abstract
Tumor progression through immune evasion is a major challenge in cancer therapy. Recent studies revealed that enhanced PD-L1 expression in cancer stem cells is linked to immune evasion. Understanding the mechanisms behind this PD-L1 overexpression in cancer stem cells is critical for developing more effective strategies for preventing immune evasion and increasing the efficacy of anti-PD-1/PD-L1 therapy. Tumorsphere formation in breast cancer cells enhanced epithelial to mesenchymal transition (EMT), which is evident by increased expression of mesenchymal markers. In this study, we analyzed CpG methylation of PD-L1 promoter in MCF-7 and BT-549 breast cancer cells and tumorspheres derived from them. PD-L1 promoter was significantly hypomethylated in MCF-7 tumorspheres, but not from BT-549 tumorspheres, compared with their cell line counterparts. The active demethylation of PD-L1 promoter was confirmed by the increase in the distribution of 5hmC and decrease in 5mC levels and the upregulation of TET3 and downregulation of DNMTs enzymes in MCF-7 tumorspheres, compared with the cell line. Additionally, we checked the distribution of repressive histones H3K9me3, H3K27me3, and active histone H3K4me3 in the PD-L1 promoter. We found that distribution of repressive histones to the PD-L1 promoter was lower in tumorspheres, compared with cell lines. Moreover, an overexpression of histone acetylation enzymes was observed in tumorspheres suggesting the active involvement of histone modifications in EMT-induced PD-L1 expression. In summary, EMT-associated overexpression of PD-L1 was partially independent of promoter CpG methylation and more likely to be dependent on posttranslational histone modifications.
Highlights
Breast cancer is the most common cancer in women accounting for 30% of all new cases reported, and it is a major cause of cancer-related death [1]
We have recently reported that programmed death-ligand 1 (PD-L1) is overexpressed in human tumor tissues and dual inhibition of signal transducers and activator of transcription 1 (STAT1) and STAT3 can downregulate PD-L1 expression [14,15,16]
We investigated epigenetic regulatory mechanisms involved in the PD-L1 expression associated with epithelial to mesenchymal transitions (EMT) in human breast cancer stem cells
Summary
Breast cancer is the most common cancer in women accounting for 30% of all new cases reported, and it is a major cause of cancer-related death [1]. As immunotherapeutic agents, showed promising outcomes with higher overall survival rate and progression-free survival, but this has been achieved in a small fraction of cancer patients [2]. Recurrence, and metastasis are still major challenges in breast cancer therapy and management, it has been reported that the presence of a subset of cells with unique features like self-renewal and differentiation called cancer stem cells (CSCs) could be a major contributor towards these challenges [3]. PDL1 overexpression plays a critical role in immune evasion through increase of T-cell apoptosis in many cancers [8]. It has recently been reported that overexpression of PD-L1 in CSCs contributes to immune evasion through
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