The role of miR-146a in melanoma progression and metastasis
Justin Mastroianni1,3*, Wolfgang Melchinger1, Heide Dierbach1 , Silke Lassman2, Robert Zeiser1,3
1University Medical Center Freiburg, Dept. of Hematology/Oncology, 79106 Freiburg;
2University of Medical Center Freiburg, Dept. of Pathology, 79106 Freiburg; 3University of Freiburg, Dept. of Biology, 79106 Freiburg
Immunotherapy has revolutionized the treatment of melanoma. Still,a better understanding of the immune response in the tumor microenvironment is crucial to improve immune checkpoint inhibitor therapy. Micro-RNAs (miRs) are small non-coding RNAs that regulate gene expression on the post-transcriptional level. miR-146a has been shown to be involved in multiple inflammatory diseases, yet its role in the melanoma microenvironment remains unclear.
Results: We aimed to clarify the role of miR-146a in the melanoma microenvironment during tumor development and progression. We found miR-146a levels increased in tumor microenviromental tissue, such as the skin, in a B16 F10 in vivo melanoma model. Furthermore, mice deficient in mir-146a survived longer and developed less metastases in comparison to wildtype animals. Both, in vitro activated miR-146a-/- T cells and T cells isolated from tumor bearing miR-146a-/- mice revealed higher expression levels of the transcription factor STAT1. In addition, those in vivo activated CD4+ and CD8+ T cells displayed a larger population of Interferon-γ (IFN-γ)+ cells. IFN-γ inhibition using a blocking antibody in this model, altered survival and metastasis patterns of the miR-146a-/- group to resemble the wildtype group.
Conclusion: The results we present here reveal the influential role of miR-146a in the tumor microenvironment of an advanced stage metastatic melanoma. The hyperactivity of the immune system deficient in miR-146a serves as a counter-measure to the disease progression, by modulation of IFN-γ production, downstream of Stat1 phosphorylation.
Our evidence indicate that endogenous miR-146a could be suppressing auto-immune control of metastasis in a murine model making it a potential target for future immunomodulating therapy.