title: Immunomodulating property of MAPK inhibitors: from translational knowledge to clinical implementation.
abstract: Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2. Furthermore, the presence of oncogenic BRAF leads to an immune suppressive phenotype characterized by the presence of inhibitory immune cells such as regulatory T cells, myeloid-derived suppressor cells, or tumor-associated macrophages, which can in turn inhibit the function of tumor-infiltrating T cells. Growing evidence suggests that, in addition to their established molecular mechanism of action, the therapeutic efficacy of BRAF inhibitors and MEK inhibitors relies on additional factors that affect the tumor-host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells. Focus of the present review is to summarize the off target mechanisms of response to BRAF inhibitors and MEK inhibitors and the synergy between targeted therapy and immunotherapy as the biological source to open a window of strategic opportunities for the design of new exciting clinical trials.
authors.affiliation: Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Logu
authors.affiliation: Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Merelli
authors.affiliation: Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
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: D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf