Mechanisms of Resistance to Immunotherapy in Cutaneous Melanoma

High tumor mutational burden and evidence of spontaneous development of adaptive immunity in a large fraction of patients explain why cutaneous melanoma is one of the most immunogenic human tumors. Strong tumor immunogenicity and pre-existing T cell-mediated immunity are also the key factors that promote responsiveness to immunotherapy targeting immune checkpoints, even in patients with advanced disease. In spite of these favorable molecular and immunological features, a variety of primary and adaptive resistance mechanisms limit the clinical benefit of immune checkpoint blockade to only a fraction of the patients. These mechanisms, that will be reviewed in this chapter, are triggered by a multitude of genetic alterations, gene programs expressed in the tumor or in immune cells, and master immunoregulatory genes. Collectively these mechanisms skew the tumor immune landscape away from the highly T cell-infiltrated profile requested for response, promote development of an immunosuppressive microenvironment, and impair all the stages of immune response development, from the early stages of dendritic cell–T cell interaction and T cell cross-priming to the late stages of therapy-dependent T cell functional rescue and tumor recognition.