While ICOS mRNA expression showed a significant association with overall survival, response to PD-1-targeted monotherapy or combined anti-PD-1 and anti-CTLA-4 ICB, and progression-free survival under ICB, we identified ICOS hypomethylation as a biomarker of poor prognosis but better response to ICB and prolonged PFS in a case/control study comprised of responders and non-responders and OS in a cohort of ICB treated melanomas. This evidence concerns the gene ICOS and melanoma.