miR-146a Controls Immune Response in the Melanoma Microenvironment

Abstract

Micro-RNAs (miR) are small non-coding RNAs that regulate gene expression, post-transcription, and manipulate immune responses in different types of cancer. In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and miR-146a-/- mice survived longer and developed less metastases in comparison to wild type melanoma-bearing mice. T cells isolated from miR-146a-/- mice revealed higher expression levels of the miR-146a target gene Stat1 and the Stat1-regulated cytokine Interferon-γ (IFN-γ). Neutralization of IFN-γ in miR-146a-/- mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFN-γ reduced melanoma cell migration, cell cycle activity, and basal metabolic rate. Conversely, IFN-γ also increased PD-L1 levels on the melanoma cells, which may counterbalance some of the beneficial effects increasing immune escape in vivo. Combined treatment with a miR-146a antagomiR and anti-PD-1 resulted in improved survival over isotype-control or anti-PD-1 treatment alone. In summary, these data show that miR-146a plays a central role within the STAT1/IFN-γ axis in the melanoma microenvironment, affecting melanoma migration, proliferation, and mitochondrial fitness as well as PD-L1 levels. Additionally, combined inhibition of PD-1 and miR-146a could be a novel strategy to enhance anti-tumor immune response elicited by checkpoint therapy.

Dihydroartemisinin inhibits melanoma by regulating CTL/Treg anti-tumor immunity and STAT3-mediated apoptosis via IL-10 dependent manner

“…In tumors, increase of IFN-g would lead to activation of the STAT3 pathway and was accompanied with increased expression of PD-L1, which was associated with poor prognosis of lung cancer [35]. IFN-g could also significantly inhibit the growth of B16 cells and increase the expression of PD-L1 by activating the STAT1 signaling pathway after treating B16 melanoma cells with IFN-g. After PD-1 antagonist was given to melanoma-bearing mice, the tumor suppressive effect of IFN-g was further enhanced [36]. In our experiments, DHA treatment significantly increased expression of IFN-g and phosphorylation of STAT1.…”

LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p/STAT1/PD-L1 axis

“…STAT1 usually acts as the transcriptional factor in the tumor immune function [27][28][29]. Studies demonstrated that STAT1 is the functional target of miRNAs [30][31][32] (miRNA-145-5p, miRNA-146A, miRNA-21), but the regulation of miRNA-382-3p and STAT1 remain unclear. To verify if STAT1 was the functional target of miR-382-3p, we first examined the expression and correlation of them.…”

Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma

“…Downregulation of miR-589 promotes cancer malignancy by increasing PD-L1 expression level (Liu et al, 2017). miR-146a, which is increased in metastatic melanoma, induces immune evasion of melanoma cells (Mastroianni et al, 2019). The combination of a miR-146a inhibitor and anti-PD-L1 improves survival in a mouse model of melanoma (Mastroianni et al, 2019).…”