Phospho-STAT1 expression as a potential biomarker for anti-PD-1/anti-PD-L1 immunotherapy for breast cancer

In the present study, we evaluated the mechanisms of programmed death ligand 1 (PD-L1) expression in the breast cancer microenvironment, focusing on the role of interferon-gamma (IFN-gamma), and the clinical indications for anti-programmed cell death 1 (PD-1) /anti-PD-L1 immunotherapy. We evaluated PD-L1 expression in 4 breast cancer cell lines in the presence of 3 types of inhibitors, as well as IFN-gamma. The expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT1), one of the IFN-gamma signaling pathway molecules, was analyzed using immunohistochemistry (IHC) in relation to PD-L1 and human leukocyte antigen (HLA) class I expression on cancer cells and tumor-infiltrating CD8-positive T cells in 111 patients with stage II/III breast cancer. Using The Cancer Genome Atlas (TCGA) database, the correlation of the IFN-gamma signature with PD-L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN-gamma was mainly involved in PD-L1 expression in the cell lines examined. IHC analysis revealed that the PD-L1 and HLA class I expression levels were significantly upregulated in the p-STAT1-positive cases. TCGA analysis indicated that the PD-L1 expression and IFN-gamma signature exhibited a positive correlation. On the whole, these findings suggest that PD-L1 and HLA class I are co-expressed in p-STAT1-positive breast cancer cells induced by IFN-gamma secreted from tumor infiltrating immune cells, and that p-STAT1 expression may be a potential biomarker for patient selection for immunotherapy with anti-PD-1/anti-PD-L1 monoclonal antibodies.