TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Simple Summary Programmed cell death ligand 1 (PD-L1) is an essential immune checkpoint molecule that helps tumor cells to escape the immune surveillance. The aim of the current study was to investigate the epigenetic mechanisms underlying the aberrant expression of PD-L1 in breast cancer cells. Here, we identified TET2 as a negative regulator of PD-L1 gene transcription in breast cancer cells. Mechanistically, TET2 recruits HDAC1/2 to the PD-L1 promoter and facilitates the deacetylation of H3K27ac, resulting to the suppression of PD-L1 gene transcription. Our work reveals an unanticipated role of TET2-HDAC1/2 complex in the regulation of PD-L1 gene expression, providing new insights into the epigenetic mechanisms that drive immune evasion during breast cancer pathogenesis. Activation of PD-1/PD-L1 checkpoint is a critical step for the immune evasion of malignant tumors including breast cancer. However, the epigenetic mechanism underlying the aberrant expression of PD-L1 in breast cancer cells remains poorly understood. To investigate the role of TET2 in the regulation of PD-L1 gene expression, quantitative reverse transcription PCR (RT-qPCR), Western blotting, chromatin immunoprecipitation (ChIP) assay and MeDIP/hMeDIP-qPCR were performed on MCF7 and MDA-MB-231 human breast cancer cells. Here, we reported that TET2 depletion upregulated PD-L1 gene expression in MCF7 cells. Conversely, ectopic expression of TET2 inhibited PD-L1 gene expression in MDA-MB-231 cells. Mechanistically, TET2 protein recruits histone deacetylases (HDACs) to PD-L1 gene promoter and orchestrates a repressive chromatin structure to suppress PD-L1 gene transcription, which is likely independent of DNA demethylation. Consistently, treatment with HDAC inhibitors upregulated PD-L1 gene expression in wild-type (WT) but not TET2 KO MCF7 cells. Furthermore, analysis of the CCLE and TCGA data showed a negative correlation between TET2 and PD-L1 expression in breast cancer. Taken together, our results identify a new epigenetic regulatory mechanism of PD-L1 gene transcription, linking the catalytic activity-independent role of TET2 to the anti-tumor immunity in breast cancer.

Automated summary

The study identified TET2 as a negative regulator of PD-L1 gene transcription in breast cancer cells, recruiting HDAC1/2 to the PD-L1 promoter to suppress PD-L1 gene expression through deacetylation of H3K27ac. This work provides new insights into the epigenetic mechanisms of immune evasion in breast cancer pathogenesis.