Title:Epidrugs in the Immunotherapy of Cutaneous and Uveal Melanoma
Volume: 17
Issue: 2
Author(s): Mario Venza, Maria Visalli, Teresa Catalano, Concetta Beninati, Diana Teti and Isabella Venza
Affiliation:
Keywords:
Epigenetics, epidrugs, immunotherapy, immune response, melanoma.
Abstract: Epigenetic modifications can affect numerous mechanisms used by neoplastic cells to evade immune
control. In melanoma epigenetic defects, caused by dysregulations in the expression of genome writers, erasers, or
readers, play a significant role in the reduced expression of molecules required for efficient immune recognition as
well as antigen presentation and processing. Alterations in gene expression were identified in tumor-associated
antigens (TAAs), human leukocyte antigen (HLA) complex, co-stimulatory/accessory molecules, antigen processing
machinery (APM), and NKG2D ligands that have shown to be silenced or down-regulated in melanoma. In agreement
with the inherent reversibility of epigenetic silencing, epigenetic drugs such as inhibitors of DNA methyltransferases
(DNMTs), histone deacetylases (HDACs), histone methyltransferase enhancer of Zeste homolog 2 (EZH2), and
modifiers of microRNA (miRNA) dysregulation or antagomirs can restore the expression of these molecules,
favouring the recognition of cancer cells by immune responses, reducing the resistance to Natural Killer (NK) and
cytotoxic T cells (CTL), and enhancing the functions of antigen presenting cells. Moreover, inhibitors of reader
proteins seem to preferentially affect the NF-kB-induced activation of pro-inflammatory cytokine genes. At present an
increasing interest is shown toward new combined therapeutic approaches employing epidrugs or new molecular
inhibitors and in vivo immunotherapies, such as vaccines and adoptive T-cell transfer (ACT). This review summarizes
the current understanding of the role of epidrugs in the modulation of molecules involved in the melanoma immune
response and focuses on their future clinical use in new therapeutic combinations for melanoma treatment.
