| First Author | Mastroianni J | Year | 2019 |
| Journal | Cancer Res | Volume | 79 |
| Issue | 1 | Pages | 183-195 |
| PubMed ID | 30425059 | Mgi Jnum | J:270093 |
| Mgi Id | MGI:6274918 | Doi | 10.1158/0008-5472.CAN-18-1397 |
| Citation | Mastroianni J, et al. (2019) miR-146a Controls Immune Response in the Melanoma Microenvironment. Cancer Res 79(1):183-195 |
| abstractText | : MicroRNAs (miR) are small noncoding RNAs that regulate gene expression, posttranscription, and manipulate immune responses in different types of cancers. 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 with 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 IFNgamma. Neutralization of IFNgamma in miR-146a(-/-) mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFNgamma reduced melanoma cell migration, cell-cycle activity, and basal metabolic rate. Conversely, IFNgamma 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/IFNgamma 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 antitumor immune response elicited by checkpoint therapy. SIGNIFICANCE: These findings identify a microRNA-based mechanism by which melanoma cells escape the immune system, providing a new therapeutic strategy to improve the current management of patients with melanoma. |
