A Commotion in the Skin: Developing Melanoma Immunotherapies

Melanomas are malignant tumors that can partly and very rarely completely regress in response to immune responses. Analyzing the mechanisms underlying this immune-mediated rejection, melanomas became leading in developing general cancer immunotherapy. This resulted in the discovery of tumor-specific neoantigens and mutations autoantigens, now called tumor-associated antigens, and their specific recognition by cytotoxic T lymphocytes. Melanomas were of key importance for the development of adoptive T-cell therapy and active tumor vaccines, namely dendritic cell vaccines. Melanoma therapy with antibodies against CTLA-4 provided the proof of concept that solid cancers can be susceptible to cancer immunotherapy, and melanoma therapy with antibodies against PD-1 resulted in the clinical breakthrough of cancer immunotherapy. Still, about half of patients die from metastatic melanoma. Combining anti‒PD-1 with anti‒CTLA-4 antibodies to increase antitumor immune responses or with targeted therapy improves the overall survival only partially. Recent data revealed a close link between defects in the IFN-γ‒dependent induction of cell cycle control genes and resistance to immunotherapy, which may allow for identifying those patients that respond to immunotherapy and to develop novel therapies, combining cancer immunotherapy with cell cycle inhibitors.