Accordingly, as a potential consequence of DNA damage events, a combination of peptide vaccination and the DNA-methylating agent dacarbazine (DTIC) has been proved able to promote the generation of highly polyfunctional PD-1high CD28negMelan-A-specific CD8+ T cells, depending on AKT signaling and on the engagement of ICOS in melanoma patients [273]. This evidence concerns the gene ICOS and melanoma.