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

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Abstract
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‑γ (IFN‑γ), 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‑γ. The expression of phosphorylated signal transducer and activator of transcription 1 (p‑STAT1), one of the IFN‑γ 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‑γ signature with PD‑L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN‑γ 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‑γ 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‑γ 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.

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