Endoplasmic reticulum stress‐induced exosomal miR‐27a‐3p promotes immune escape in breast cancer via regulating PD‐L1 expression in macrophages

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 17; pp. 9560 - 9573
• Main Authors: Yao, Xiaoli, Tu, Yi, Xu, Yulin, Guo, Yueyue, Yao, Feng, Zhang, Xinghua
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.09.2020; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antibodies; Apoptosis; Apoptosis - genetics; Apoptosis - immunology; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Binding sites; Bioinformatics; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Breast cancer; CD3 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell culture; Cell death; Cell Line, Tumor; Ectopic expression; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Endoplasmic Reticulum Stress - immunology; Exosomes; Exosomes - genetics; Exosomes - immunology; Female; Fluorides; Gene expression; Homeostasis; Humans; Immune evasion; Interleukin-2 - genetics; Interleukin-2 - immunology; Kinases; Lymphocytes T; Macrophages; Macrophages - immunology; MCF-7 Cells; Medical screening; Metastasis; MicroRNAs; MicroRNAs - genetics; MicroRNAs - immunology; MicroRNA‐27a‐3p; Middle Aged; miRNA; Original; Patients; PD-L1 protein; Plasmids; programmed cell death‐Ligand 1; Protein expression; Proteins; PTEN protein; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Tumor Escape - genetics; Tumor Escape - immunology; Tumor microenvironment; Tumors; tumour immune evasion of breast cancer cells; Beijing China; New York; United Kingdom > UK; United States > US; China; Japan; macrophages; exosomes; MicroRNA-27a-3p; breast cancer; tumour immune evasion of breast cancer cells; endoplasmic reticulum; programmed cell death-Ligand 1
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15367

Immune escape of breast cancer cells contributes to breast cancer pathogenesis. Tumour microenvironment stresses that disrupt protein homeostasis can produce endoplasmic reticulum (ER) stress. The miRNA‐mediated translational repression of mRNAs has been extensively studied in regulating immune escape and ER stress in human cancers. In this study, we identified a novel microRNA (miR)‐27a‐3p and investigated its mechanistic role in promoting immune evasion. The binding affinity between miR‐27a‐3p and MAGI2 was predicted using bioinformatic analysis and verified by dual‐luciferase reporter assay. Ectopic expression and inhibition of miR‐27a‐3p in breast cancer cells were achieved by transduction with mimics and inhibitors. Besides, artificial modulation of MAGI2 and PTEN was done to explore their function in ER stress and immune escape of cancer cells. Of note, exosomes were derived from cancer cells and co‐cultured with macrophages for mechanistic studies. The experimental data suggested that ER stress biomarkers including GRP78, PERK, ATF6, IRE1α and PD‐L1 were overexpressed in breast cancer tissues relative to paracancerous tissues. Endoplasmic reticulum stress promoted exosome secretion and elevated exosomal miR‐27a‐3p expression. Elevation of miR‐27a‐3p and PD‐L1 levels in macrophages was observed in response to exosomes‐overexpressing miR‐27a‐3p in vivo and in vitro. miR‐27a‐3p could target and negatively regulate MAGI2, while MAGI2 down‐regulated PD‐L1 by up‐regulating PTEN to inactivate PI3K/AKT signalling pathway. Less CD4+, CD8+ T cells and IL‐2, and T cells apoptosis were observed in response to co‐culture of macrophages and CD3+ T cells. Conjointly, exosomal miR‐27a‐3p promotes immune evasion by up‐regulating PD‐L1 via MAGI2/PTEN/PI3K axis in breast cancer.