Regulation of major histocompatibility complex class-I (MHC-I) gene methylation using DNA methyltransferase inhibitor and PD-L1 inhibitor in triple negative breast cancer

There are few studies on the effect of DNA methyltransferase (DNMT) inhibitors and immunotherapy on major histocompatibility complex class-I (MHC-I) gene methylation in triple negative breast cancer (TNBC). The relationship between the expression of MHC-I and DNA methylation was analyzed using data from The Cancer Genome Atlas (TCGA). The expression of DNMTs and MHC-I, and DNA methylation status of MHC-I genes was analyzed in TNBC cell lines. TNBC cell lines were treated with DNMT inhibitors and programmed cell death-ligand 1 (PD-L1) inhibitor. Then, changes in the expression of DNMT and MHC-I, and methylation patterns of MHC-I genes were analyzed. TCGA data analysis confirmed that there was an inverse correlation between DNA methylation and expression of MHC-I. After treating TNBC cell lines with DNMT inhibitors and PD-L1 inhibitor alone as well as in combination, the DNA methylation pattern of the HLA-B and HLA-C gene was suppressed, but not the HLA-A gene. After Decitabine treatment, MHC-I expression was increased in BT-20, while after Zebularine treatment, it was increased only in BT-549. MHC-I expression was increased in BT-549 after Atezolizumab treatment, and in MDA-MB231 after co-administration of Decitabine and Atezolizumab. The effects of DNMT inhibitors and PD-L1 inhibitor were different depending on the TNBC cell lines and the types of drugs, suggesting that the treatment target needs to be applied differently. Further study is needed to determine specific treatment targets and appropriate drugs according to the characteristics of TNBC.