Contrasting effects on HLA and PD-L1 expression through inhibition of MAPK pathway in triple negative breast cancer cells

Abstract

Expression of human leukocyte antigen (HLA) molecules is essential for antitumour immune responses. Interferon gamma (IFN-γ) up-regulates HLA and, paradoxically, programmed cell death ligand-1 (PD-L1), which inhibits immune activation. The mitogen-activated protein kinase pathway (MAPK), overactivated in triple negative breast cancer (TNBC), is implicated in HLA and PD-L1 expression. We hypothesized that its inhibition may modulate HLA and PD-L1 expression in TNBC. Human TNBC and non-TNBC cell lines were treated with various MEK inhibitors (MEKi) in the presence/absence of IFN-γ. Flow cytometry, immunofluorescence and Western blotting were used to assess MEKi mediated changes in constitutive and inducible HLA and PD-L1 expression. U0126 antagonized cell surface HLA expression, but not total HLA protein, while the clinically relevant MEKi(s), Trametinib and Selumetinib, generally augmented constitutive and inducible cell surface HLA class I. All MEKi (s) reduced PD-L1 expression. These results have important implications for MEKi in targeting immunotherapy for TNBC.