In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies.,This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients.,Despite these successes, treatment failure seems near inevitable in the majority of cases-even in individuals treated with the BRAF/MEK inhibitor doublet.,In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma.,We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.
The paradoxical coexistence of spontaneous tumor antigen-specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction.,In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8+ T cells that up-regulate PD-1 expression.,We also observed that PD-1 regulates NY-ESO-1-specific CD8+ T cell expansion upon chronic antigen stimulation.,In the present study, we show that a fraction of PD-1+ NY-ESO-1-specific CD8+ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3+PD-1+ NY-ESO-1-specific CD8+ T cells are more dysfunctional than Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1-specific CD8+ T cells, producing less IFN-γ, TNF, and IL-2.,Tim-3-Tim-3L blockade enhanced cytokine production by NY-ESO-1-specific CD8+ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity.,In addition, Tim-3-Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8+ T cells upon prolonged antigen stimulation and acted in synergy with PD-1-PD-L1 blockade.,Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.