The complex relationship between MITF and the immune system: a Melanoma ImmunoTherapy (response) Factor?

Abstract

The clinical benefit of immune checkpoint inhibitory therapy (ICT) in advanced melanomas is limited by primary and acquired resistance. The molecular determinants of the resistance have been extensively studied, but these discoveries have not yet been translated into therapeutic benefits. As such, a paradigm shift in melanoma treatment, to surmount the therapeutic impasses linked to the resistance, is an important ongoing challenge.This review outlines the multifaceted interplay between microphthalmia-associated transcription factor (MITF), a major determinant of the biology of melanoma cells, and the immune system. In melanomas, MITF functions downstream oncogenic pathways and microenvironment stimuli that restrain the immune responses. We highlight how MITF, by controlling differentiation and genome integrity, may regulate melanoma-specific antigen expression by interfering with the endolysosomal pathway, KARS1, and antigen processing and presentation. MITF also modulates the expression of coinhibitory receptors, i.e., PD-L1 and HVEM, and the production of an inflammatory secretome, which directly affects the infiltration and/or activation of the immune cells.Furthermore, MITF is also a key determinant of melanoma cell plasticity and tumor heterogeneity, which are undoubtedly one of the major hurdles for an effective immunotherapy. Finally, we briefly discuss the role of MITF in kidney cancer, where it also plays a key role, and in immune cells, establishing MITF as a central mediator in the regulation of immune responses in melanoma and other cancers.We propose that a better understanding of MITF and immune system intersections could help in the tailoring of current ICT in melanomas and pave the way for clinical benefits and long-lasting responses.

Protocatechuic Aldehyde Inhibits α-MSH-Induced Melanogenesis in B16F10 Melanoma Cells via PKA/CREB-Associated MITF Downregulation

“…MITF is recognized as a major regulator of melanoma progression, but it can regulate multiple biological processes in melanoma cells, such as suppression of metastasis, differentiation, proliferation, migration, and senescence [ 36 ]. The increased MITF expression is associated with melanoma differentiation and proliferation, whereas decreased MITF expression is associated with a melanoma dedifferentiation [ 37 ]. The present study shows that PA downregulated MITF expression.…”

Tumor Immune Microenvironment Characterization Identifies Prognosis and Immunotherapy-Related Gene Signatures in Melanoma

“…Approximately 324,635 incident cases and 57,043 related deaths were reported worldwide in 2020 ( 1 ). In the past decades, immune checkpoint inhibitor therapy targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death receptor 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have resulted in impressive outcomes in patients with malignant melanoma ( 2 ). However, approximately 40–65% of melanoma patients have no response to or develop relapse after anti-PD-1 therapy due to primary or acquired resistance, and over 70% of patients experience anti-CTLA-4 treatment failure ( 3 ).…”

Immune Checkpoints in Cancers: From Signaling to the Clinic

“…This signature is mainly composed of genes involved in EMT (such as AXL TWIST2), immunosuppressive genes (CCL2, CCL8) and interestingly, a number of genes that are regulated by MITF, the master regulator of melanocyte differentiation that is also implicated in melanoma migration, survival and stemness. This aspect is developed in [ 148 ].…”

“…One protein that is critical to the phenotypic plasticity and resistance mechanisms in melanoma is the transcription factor MITF, the master regulator of melanocyte homeostasis [ 157 , 158 , 159 ]. Furthermore, MITF impacts immune function [ 148 ]. Interestingly, we recently showed that MITF controls the expression of ITGBL1.…”