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

Abstract

Background 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. Herein, we aim to characterize the role of miR-21 in regulating the accumulation and activity of MDSCs in lung cancer. Methods The 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. Results MiR-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. Conclusions Taken together, the study provides evidence that targeting miR-21 in MDSCs may be developed as an immunotherapeutic approach to combat lung cancer development.

miRSCAPE - Inferring miRNA expression in single-cell clusters

“…However, in contrast to the epithelial cells, miRSCAPE predicts miR-21 as down-regulated in the myeloid cells of the tumor. This may represent a normal immune response consistent with a previous finding that miR-21 inhibition reduces the proportion of myeloid-derived suppressor cells in lung cancer 47 . Interestingly, miR-21 is also known to promote proliferation in AML 48 .…”

Dysregulated Expression of Arterial MicroRNAs and Their Target Gene Networks in Temporal Arteries of Treatment-Naïve Patients with Giant Cell Arteritis

“…Our results point to upregulated YAP1 and downregulated KLF4 mRNAs in GCA TABs, however whether these factors mechanistically interact in diseased arteries to drive GCA pathology needs to be further elucidated. Furthermore, YAP1 expression corelated positively with miR-21 levels and miR-21-driven RUNX1 repression led to elevated YAP expression in myeloid-derived suppressor cells [ 69 ].…”

Myeloid-Derived Suppressor Cells in Solid Tumors

“…ADAM17 (a disintegrin and metalloproteinase domain 17), expressed on MDSCs, is likely to down-regulate L-selection on CD4 + and CD8 + T cells and prevent them to migrate to peripheral lymph nodes and tumor sites [ 5 ]. Furthermore, some small single-stranded non-coding RNA, such as microRNA-21 and microRNA-155, were also shown to adjust the immune suppression system mediated by MDSCs in tumors [ 46 , 47 ].…”