title: Immunotolerance as a Mechanism of Resistance to Targeted Therapies in Melanoma.
abstract: The therapy of metastatic melanoma (MM) was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in ≈40-50% of patients. Oncogenic BRAF promotes an immune-compromised tumour microenvironment (TME). Inhibition of MAPK pathway signaling with BRAF (BRAFi) and MEK inhibitors (MEKi) attenuates immune escape and increases the melanoma immunogenicity through multiple mechanisms, including elevation of melanoma antigen expression and improved T cell infiltration and function. These changes sustain the TME for response to immunotherapy. In this chapter we discuss preclinical and clinical data supporting the immunomodulating activities of targeted therapies, the immunotolerance as a mechanisms of resistance and highlight the rationale for novel combinations of targeted therapies and immunotherapies with the potential to significantly improve the future treatment of MM patients.
authors.affiliation: Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy. mariomandala@tin.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Massi
mesh_terms: D019008:Drug Resistance, Neoplasm; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D008545:Melanoma / Q000188:drug therapy*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; BRAF inhibitors; Immunotolerance; MEK inhibitors; Resistance