Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages

Hepatology - Tập 70 Số 1 - Trang 241-258 - 2019
Jiatao Liu1,2, Jingwei Shao1, Hanqing Yu1, Ju Zhang1, Yong He3, Dechun Feng3, Fang Wang1, Xiaoqiu Li1, Qingqing Liu1, Yuhuan Li1, Zhenli Guo1, Bin Gao3, Wei Wei4, Hua Wang1,5, Guoping Sun1
1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
2Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China
3Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
4Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
5Institute for Liver Diseases of Anhui Medical University, Hefei, China

Tóm tắt

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD‐L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose‐regulated protein 78, activating transcription factor 6, protein kinase R–like ER kinase, and inositol‐requiring enzyme 1α) was up‐regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress–related proteins positively correlated with CD68+ macrophage recruitment and PD‐L1 expression in HCC tissues. High‐throughput sequencing analysis identified miR‐23a‐3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)‐treated HCC cells (Exo‐TMs). miR‐23a‐3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo‐TMs up‐regulated the expression of PD‐L1 in macrophages in vitro and in vivo. Bioinformatics analysis suggests that miR‐23a‐3p regulates PD‐L1 expression through the phosphatase and tensin homolog (PTEN)–phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR‐23a‐3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD‐L1 expression in macrophages. Finally, coculture of T cells with Exo‐TM–stimulated macrophages decreased CD8+ T‐cell ratio and interleukin‐2 production but increased T‐cell apoptosis in vitro. Conclusion: ER‐stressed HCC cells release exosomes to up‐regulate PD‐L1 expression in macrophages, which subsequently inhibits T‐cell function through an exosome miR‐23a–PTEN–AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.

Từ khóa


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Hepatology

Tập 70 Số 1

241-258

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