MiR-6991-3p is identified as a novel suppressor in the expansion and activation of myeloid-derived suppressor cells in hepatoma-bearing mice

Abstract

ObjectiveMyeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells derived from bone marrow, which has a significant ability in inhibition of immune cell response. In this study, the role of miR-6991-3p in regulating function of MDSCs was investigated.MethodsMDSCs were isolated from different tissues of the control and hepatoma-bearing mice, and then expression of miR-6991-3p was detected with qPCR. Then, the miR-6991-3p mimic and inhibitor were respectively transfected into MDSCs, and behaviors of MDSCs were evaluated, including expansion, apoptosis, and production of inflammatory factors. Furthermore, we explored the underlying mechanism from which miR-6991-3p regulated MDSC functions.ResultsExpression miR-6991-3p was markedly decreased in the MDSCs derived from spleen and further decreased in the MDSCs derived from the tumor tissue. MiR-6991-3p mimic transfection suppressed expansion and promoted apoptosis of MDSCs, accompanied by a significant decrease in the production of IL-6 and GM-CSF that are identified as stimulators in MDSC expansion. In contrast, miR-6991-3p inhibitor transfection displayed the opposite effect. miR-6991-3p bound with and negatively regulated expression of LGALS9, a newly identified immune checkpoint gene and activator of STAT3, suppressing production of multiple factors that were customarily used to characterize the activation of MDSCs. MiR-6991-3p-accommodated MDSCs displayed less suppression on T cells, while miR-6991-3p inhibitor enhanced the suppression of MDSCs on T cells.ConclusionMiR-6991-3p is identified as a novel suppressor in the expansion and activation of myeloid-derived suppressor cells, which may be regarded as a promising target for modulating the function of MDSCs.

Interaction Between microRNAs and Myeloid-Derived Suppressor Cells in Tumor Microenvironment

“…miR-6991-3p was markedly reduced in MDSCs from the tumor microenvironment, which means that miR-6991-3P repressed the MDSC expansion and function of inhibiting T-cell proliferation. STAT3 was proved to be the direct target of mir-66991-3p ( 33 ). On the contrary, miR-155 and miR-21 synergistically upregulated STAT3 expression indirectly by targeting SHIP-1 and PTEN, respectively, and eventually enhanced the function and expansion of MDSCs.…”

MicroRNA networks regulate the differentiation, expansion and suppression function of myeloid-derived suppressor cells in tumor microenvironment

“…miR-10a activated AMPK signaling to promote expansion and activation of MDSCs in breast cancer cells with chemotherapy-induced immune resistance 21. miR-6991-3p could directly target the immune checkpoint gene LGALS9 (Galectin 9) and MiR-6991-3p mimic transfection suppressed expansion and promoted apoptosis of MDSCs through suppressing LGALS9-mediated activation of Janus kinase (JAK) and STAT3 22. In B lymphoma -bearing mice, miR-30a expression was increased in both G-MDSCs and M-MDSCs.…”

<p>G-MDSCs-Derived Exosomal miRNA-143-3p Promotes Proliferation via Targeting of ITM2B in Lung Cancer</p>

“…6 G-MDSCs mediate immune suppression function through increasing the levels of nitric oxide (NO) synthase, arginase 1 (Arg-1), and reactive oxygen species (ROS). 7 G-MDSCs can also promote lung cancer progression by other ways, such as through exosomes. 8 Exosomes are extracellular membrane vesicles that contain proteins and nucleic acid.…”