The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα.
The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα.
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DOI：
10.1158/2159-8290.cd-13-1007
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发表时间：
2014-10
期刊：
影响因子：
28.2
通讯作者：
Wellbrock C
中科院分区：
文献类型：
--
作者：
Smith MP;Sanchez-Laorden B;O'Brien K;Brunton H;Ferguson J;Young H;Dhomen N;Flaherty KT;Frederick DT;Cooper ZA;Wargo JA;Marais R;Wellbrock C
最近，靶向治疗与免疫治疗相结合的基本原理已逐渐明朗，但我们对MAPK通路抑制剂治疗期间的免疫反应的理解有限。我们发现免疫微环境可以作为MAPK途径靶向治疗的耐药性来源，而且在治疗过程中这种来源会得到加强。特别是，我们发现巨噬细胞来源的TNFα是一种重要的黑色素瘤生长因子，通过谱系转录因子MITF提供对MAPK通路抑制剂的抗性。最引人注目的是，在BRAF突变型黑色素瘤患者和brafv600e -黑色素瘤异体移植物中，MAPK通路抑制剂增加了肿瘤相关巨噬细胞的数量，以及TNFα和MITF的表达。用i - κ b激酶抑制剂抑制tnf α-信号，不仅可以靶向黑色素瘤细胞，还可以靶向微环境，从而大大增强了MAPK通路抑制剂的疗效。总之，我们发现免疫微环境是一种新的耐药性来源，并揭示了一种新的策略来提高黑色素瘤靶向治疗的疗效。
Recently the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune-microenvironment can act as source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma-growth factor that provides resistance to MAPK pathway inhibitors through the lineage-transcription factor MITF. Most strikingly, in BRAF mutant melanomas of patients and BRafV600E-melanoma allografts MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNFα and MITF expression. Inhibiting TNFα-signaling with IκB-kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells, but also the microenvironment. In summary, we identify the immune-microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma.