The theory that 17-β-estrogen (E2) is a potent immunomodulator was proposed decades ago. Many genes in cells of the innate and adaptive immune systems are regulated by E2 through E2 receptor (ER). Among these genes, the expression and promoter activity of IFN-γ was reported to be increased by 10-9 M E2 treatment (1). It is well known that E2 may promote ER+ breast cancer development. Human cancer cells constitutively express PD-L1 (programmed death ligand-1) on cell surface, and its expression is greatly upregulated by IFN-γ. The upregulation of PD-L1 on cancer cells allows them to escape immune surveillance by inhibiting cancer-specific cytotoxic T lymphocytes (CTLs) through binding to T cell surface receptor PD-1. In lung cancer cell lines, it was determined that the mechanism underlying IFN-γ-stimulated PD-L1 expression involved interferon regulatory factor-1(IRF-1)-activated JAK/STAT pathways (2). IRF-1 is downregulated by E2 in murine spleenocytes (3) and MCF-7 breast cancer cell line (4). We hypothesized that PD-L1 expression on tumor cells may be downregulated by E2, which supports the observation that ER+ breast cancers are generally less malignant with better prognosis. However, a recent study demonstrated that 10 nM E2 upregulated PD-L1 protein expression in the endometrial cancer cell line Ishikawa and MCF-7 cells, but not in MDA-MB-231 ER negative (ER-) breast cancer cells, via the PI3K/AKT pathways (5). To clarify the contradiction between our hypothesis and the reported data, we demonstrated in vitro by flow cytometry that E2 reduced the functional PD-L1 surface expression in ER+ MCF-7 cells but not in ER- MDA-MB-231 cells. ERα inhibitors (e.g. tamoxifen) did not affect the stimulation of PD-L1 expression by IFN-γ. ERβ blocker is currently being tested to confirm the involvement of β subunit. The possible signal pathways that may contribute to such inhibition of IFN- γ stimulated surface PD-L1 expression are under investigation.