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miR-146a Controls Immune Response in the Melanoma Microenvironment
- Source :
- Cancer Research. 79:183-195
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
Abstract
- 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 IFNγ. Neutralization of IFNγ in miR-146a−/− mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFNγ reduced melanoma cell migration, cell-cycle activity, and basal metabolic rate. Conversely, IFNγ 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/IFNγ 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.
- Subjects :
- 0301 basic medicine
Cancer Research
medicine.medical_treatment
Biology
B7-H1 Antigen
Article
Interferon-gamma
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Cell Movement
Interferon
Tumor Cells, Cultured
Tumor Microenvironment
medicine
Animals
Humans
Interferon gamma
Melanoma
Skin
Mice, Knockout
Regulation of gene expression
Cell migration
Cell cycle
Prognosis
medicine.disease
3. Good health
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
MicroRNAs
STAT1 Transcription Factor
030104 developmental biology
Cytokine
Oncology
Case-Control Studies
030220 oncology & carcinogenesis
Cancer research
medicine.drug
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....1ff50d778ad3b062693a11718fe8b31a