MITF induces escape from innate immunity in melanoma

Abstract

Background The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. Methods By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. Results Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. Conclusion Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance

“…In particular, they were able to identify TNF-α as the crucial factor responsible for the transient dedifferentiation in response to T cell therapy [128]. Recently, an interesting study elucidated the role of MITF in resistance to innate immunity in melanoma and identified it as a transcriptional regulator of ADAM metallopeptidase domain 10 (ADAM10) [129]. ADAM10 is a membrane-anchored metalloprotease [130] that cleaves the natural killer group 2, member D (NKG2D) ligands MHC class I polypeptide-related sequence A (MICA), and to a lesser extend MHC class I polypeptide-related sequence B (MICB) [131,132].…”

“…ADAM10 is a membrane-anchored metalloprotease [130] that cleaves the natural killer group 2, member D (NKG2D) ligands MHC class I polypeptide-related sequence A (MICA), and to a lesser extend MHC class I polypeptide-related sequence B (MICB) [131,132]. Thus, MITF-dependent upregulation of ADAM10 impairs melanoma cell recognition by natural killer (NK) cells, resulting in the escape of MITF high expressing cells [129].…”

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…However, cells can evade immune detection by proteolytic shedding of the cell surface ligands MICA and MICB by the action of disulfide isomerase (ERp5) and several proteases of the matrix metalloproteinases (MMPs) and ADAMs (a disintegrin and metalloproteinases) enzyme families. It was recently demonstrated that the oncoprotein MITF (Melanocyte-Inducing Transcription Factor) regulates the expression of ADAM10 that cleaves MICA/B allowing cells to bypass NK cell surveillance [542]. Antibodies targeting MICA/B prevent proteolytic shedding and maintain immunoactivity [543].…”

Low Doses of Celecoxib Might Promote Phenotype Switching in Cutaneous Melanoma Treated with Dabrafenib—Preliminary Study

“…It also includes a differentiation/de-differentiation switch linked to the expression of the microphthalmia transcription factor (MITF) and receptor tyrosine kinase AXL, as well as changes in proliferation rates. MITF is essential for melanocyte development, it regulates the expression of pigment-producing enzymes and also plays a central role in melanoma: it induces the escape from innate immunity, reprograms focal adhesion and the extracellular matrix, and regulates starvation-induced autophagy [ 3 , 4 , 5 ]. BRAF regulates MITF expression via PAX3 and BRN2 transcription factors, which act as a rheostat [ 6 ].…”