Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). The study aimed to identify miRNAs that posttranscriptionally control PD-L1 expression on tumor cells and also regulate immune evasion. A comprehensive miRNA screening using The Cancer Genome Atlas (TCGA) dataset (n ¼ 260) combined with eight different miRNA target prediction programs resulted in the identification of a tumor suppressive miRNA, miR-148a-3p, as a potential negative regulator of PD-L1 expression, particularly in dMMR/MSI-H colorectal cancer. Using multiple cohorts of colorectal cancer, including TCGA data, a microarray dataset (n ¼ 148), and formalin-fixed, paraffin-embedded samples (n ¼ 395), we found that the expression of miR-148a-3p was decreased in dMMR/MSI-H tumors, correlating inversely with PD-L1 levels. We demonstrate that miR-148a-3p directly binds to the 3 0 -untranslated region of PD-L1, thereby reducing whole-cell and cell surface PD-L1 levels in HCT116 and SW837 cell lines. Overexpression of miR-148a-3p repressed IFNg-induced PD-L1 expression on tumor cells and consequently diminished T-cell apoptosis in a coculture model of IL2-activated T cells and IFNg-treated tumor cells. In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer.
Implications:This study provides novel evidence that miR-148a-3p negatively regulates tumor cell PD-L1 expression and decreased levels of miR-148a-3p contributes to the immunosuppressive tumor microenvironment.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.