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.
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Biechele TL, Kulikauskas RM, Toroni RA et al (2012) Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Sci Signal 5(206):ra3
Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516
Das Thakur M, Salangsang F, Landman AS et al (2013) Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494(7436):251–255
Falchook GS, Long GV, Kurzrock R et al (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379(9829):1893–1901
Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819
Flaherty KT, Robert C, Hersey P et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367(2):107–114
Frederick DT, Piris A, Cogdill AP et al (2013) BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 19(5):1225–1231
Gray-Schopfer VC, Karasarides M, Hayward R, Marais R (2007) Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res 67(1):122–129. Erratum in: Cancer Res. 2007; 67(4):1877
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Haq R, Yokoyama S, Hawryluk EB et al (2013) BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc Natl Acad Sci U S A 110(11):4321–4326
Hauschild A, Grob JJ, Demidov LV et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365
Hugo W, Shi H, Sun L et al (2015) Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162(6):1271–1285
Hu-Lieskovan S, Mok S, Homet Moreno B et al (2015) Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med 7(279):279ra41
Johannessen CM, Boehm JS, Kim SY et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326):968–972
Johansen LL, Lock-Andersen J, Hviid TV (2016) The pathophysiological impact of HLA class Ia and HLA-G expression and regulatory T cells in malignant melanoma: a review. J Immunol Res 2016:6829283
Khalili JS, Liu S, Rodríguez-Cruz TG et al (2012) Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res 18(19):5329–5340
Larkin J, Ascierto PA, Dréno B et al (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371(20):1867–1876
Long GV, Stroyakovskiy D, Gogas H et al (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386(9992):444–451
Mandalà M, De Logu F, Merelli B, Nassini R, Massi D (2016) Immunomodulating property of MAPK inhibitors: from translational knowledge to clinical implementation. Lab Investig. doi:10.1038/labinvest.2016.132. [Epub ahead of print]
Massi D, Brusa D, Merelli B et al (2014) PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics. Ann Oncol 25(12):2433–2442
Massi D, Brusa D, Merelli B et al (2015) The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. Ann Oncol 26(9):1980–1987
Menzies AM, Long GV (2014) Systemic treatment for BRAF-mutant melanoma: where do we go next? Lancet Oncol 15(9):e371–e381
Merelli B, Massi D, Cattaneo L, Mandalà M (2014) Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol 89(1):140–165
Ribas A, Hamid O, Daud A et al (2016) Association of Pembrolizumab with Tumor Response and Survival Among Patients with Advanced Melanoma. JAMA 315(15):1600–1609. Erratum in: JAMA 2016 Jun 14;315(22):2472
Robert C, Karaszewska B, Schachter J et al (2015a) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372(1):30–39
Robert C, Schachter J, Long GV et al (2015b) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532
Schadendorf D, Hodi FS, Robert C et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894
Smith MP, Sanchez-Laorden B, O'Brien K et al (2014) The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα. Cancer Discov 4(10):1214–1229
Smyth MJ, Ngiow SF, Ribas A, Teng MW (2016) Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 13(3):143–158
Sosman JA, Kim KB, Schuchter L et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366(8):707–714
Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523(7559):231–235
Straussman R, Morikawa T, Shee K et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504
Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203(7):1651–1656
Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145
Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571
Wargo JA, Cooper ZA, Flaherty KT (2014) Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov 4(12):1377–1386
Wilmott JS, Long GV, Howle JR et al (2012) Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 18(5):1386–1394
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Mandalà, M., Massi, D. (2017). Immunotolerance as a Mechanism of Resistance to Targeted Therapies in Melanoma. In: Mandalà, M., Romano, E. (eds) Mechanisms of Drug Resistance in Cancer Therapy. Handbook of Experimental Pharmacology, vol 249. Springer, Cham. https://doi.org/10.1007/164_2017_5
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