Immunotolerance as a Mechanism of Resistance to Targeted Therapies in Melanoma

  • Mario MandalàEmail author
  • Daniela Massi
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


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.


BRAF BRAF inhibitors Immunotolerance MEK inhibitors Resistance 


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Unit of Medical Oncology, Department of Oncology and HaematologyPapa Giovanni XXIII Cancer Center HospitalBergamoItaly
  2. 2.Division of Pathological Anatomy, Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly

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