Mandalà Mario, Massi Daniela
Unit of Medical Oncology, Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Piazza OMS 1, 24100, Bergamo, Italy.
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Handb Exp Pharmacol. 2018;249:129-143. doi: 10.1007/164_2017_5.
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抑制剂的引入彻底改变了转移性黑色素瘤（MM）的治疗方法，BRAF是一种致癌基因，约40%-50%的患者中存在该基因的突变。致癌性BRAF会促进免疫功能受损的肿瘤微环境（TME）。使用BRAF抑制剂（BRAFi）和MEK抑制剂（MEKi）抑制MAPK信号通路，可通过多种机制减弱免疫逃逸并增加黑色素瘤的免疫原性，包括提高黑色素瘤抗原表达、改善T细胞浸润和功能。这些变化维持了TME对免疫治疗的反应。在本章中，我们讨论支持靶向治疗免疫调节活性的临床前和临床数据、作为耐药机制的免疫耐受，并强调靶向治疗与免疫治疗新联合方案的基本原理，这些联合方案有可能显著改善MM患者未来的治疗。
