MiR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer

Danhua Qu,Jie Zhang,Yanjun Wang,Guangping Meng,Jinying Wei

doi:10.1186/s12935-020-01555-7

Abstract

BackgroundMyeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in tumor microenvironment and favor solid tumor growth. Herein, we aim to characterize the role of miR-21 in regulating the accumulation and activity of MDSCs in lung cancer.MethodsThe proportions of MDSCs, T helper cells (Th), and cytotoxic T lymphocytes (CTL) were evaluated by flow cytometric analyses of peripheral blood and tumor tissues collected from Lewis lung-cancer-bearing mice. T cell proliferation assay was performed in CD4+ or CD8+ T cells cocultured with MDSCs. MDSC apoptosis was examined by flow cytometric analysis. The levels of IL-10, TGF-β, and GM-CSF in mouse serum were determined by ELISA. miR-21 targeting RUNX1 and RUNX1 interaction with YAP were evaluated by RIP, dual-luciferase reporter gene, and ChIP assays.ResultsMiR-21 inhibition by its antagomir reduced the proportion of MDSCs, increased the proportion of Th and CTL in peripheral blood and tumor tissues of Lewis lung-cancer-bearing mice, protected Th and CTL from the suppression of MDSCs, increased apoptosis of MDSCs, but reduced IL-10, TGF-β and GM-CSF levels in mouse serum. RUNX1 could transcriptionally inhibit the YAP expression, whereas miR-21 targeting RUNX1 led to elevated YAP expression levels. Mechanistic investigation showed that miR-21 maintained MDSC accumulation in tumor microenvironment and promoted immunosuppressive ability of MDSCs in Lewis lung-cancer-bearing mice by down-regulating RUNX1and up-regulating YAP.ConclusionsTaken together, the study provides evidence that targeting miR-21 in MDSCs may be developed as an immunotherapeutic approach to combat lung cancer development.

Highlights

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer
In order to determine the expression patterns of miR-21 in lung cancer, a box line map was plotted by extracting the expression data of miR-21 of dataset GSE63805, which revealed that miR-21 was overexpressed in the lung cancer samples (Fig. 1b)
Our findings suggested that miR-21 can up-regulate the expression levels of Yes-associated protein (YAP) by targeting RUNX1 to regulate the immunosuppressive ability of MDSCs in lung cancer

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in tumor microenvironment and favor solid tumor growth. Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immune cells from the myeloid lineage, which serve as suppressors of antitumor immunity, have been found to contribute to the immunosuppressive microenvironment during tumor development [5]. Studies have shown that targeting MDSC recruitment and enhancing antitumor immunity can augment the therapeutic efficacy of ablative hypofractionated radiation therapy in subcutaneous tumors using syngeneic lung cancer [7]. Increasing evidence has further shown that microRNAs (miRNAs), such as miR-494 and miR-155, influence tumor-expanded MDSC accumulation, and function in tumor microenvironment and favor solid tumor growth [8, 9]

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