DNA Methyltransferase Inhibition Upregulates the Costimulatory Molecule ICAM-1 and the Immunogenic Phenotype of Melanoma Cells.

In cutaneous melanoma, epigenetic dysregulation is implicated in drug resistance and tumor immune escape. However, the epigenetic mechanisms that influence immune escape remain poorly understood. To elucidate how epigenetic dysregulation alters the expression of surface proteins that may be involved in drug targeting and immune escape, we performed a 3-dimensional surfaceome screen in primary melanoma cultures and identified the DNA-methyltransferase inhibitor decitabine as significantly upregulating the costimulatory molecule ICAM-1. By analyzing The Cancer Genome Atlas melanoma dataset, we further propose ICAM-1 upregulation on melanoma cells as a biomarker of a proinflammatory and antitumorigenic signature. Specifically, we showed that DNA-methyltransferase inhibitor administration upregulated the expression of the antigen-presenting machinery, HLA class I/II, as well as the secretion of the proinflammatory chemokines CXCL9 and CXCL10. Our in silico analysis on The Cancer Genome Atlas and ex vivo experiments on human primary melanoma samples revealed that increased ICAM-1 expression positively correlated with increased immunogenicity of human melanoma cells and correlated with increased immune cell infiltration. These findings suggest a therapeutic approach to modulate the immunogenic phenotype of melanoma cells, hence supporting the exploration of DNA-methyltransferase inhibitor as a potential inducer of infiltration in immunologically cold tumors.