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首页> 外文期刊>Journal of experimental & clinical cancer research : >MITF induces escape from innate immunity in melanoma
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MITF induces escape from innate immunity in melanoma

机译：Mitf诱导逃离黑色素瘤的先天免疫力

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The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.
机译：免疫基疗法的应用彻底改变了癌症治疗。然而，免疫系统如何应对肿瘤内的表型异构群体令人难以理解。在黑色素瘤中，表型身份的主要决定因素之一是谱系存活oncogene MITF，其集成了不同的微环境提示，以协调黑色素瘤生存，衰老旁路，分化，增殖，侵袭，代谢和DNA损伤修复。 MITF还控制免疫反应是否未知。通过使用几种小鼠黑色素瘤模型，我们研究了MITF调节抗黑色素瘤免疫应答的潜在作用。 CHIP-SEQ数据分析，CHIP-QPCR，CRISPR-CAS9基因组编辑和荧光素酶报告结果用于鉴定ADAM10作为直接MITF靶基因。用于蛋白质印迹，共聚焦显微镜，流式细胞术和自然杀伤（NK）细胞毒性测定来确定MITF驱动的表型可塑性调节黑素瘤NK细胞介导的杀灭的潜在机制。在这里，我们表明MITF调节ADAM10的表达，这是一种关键的脱落酶，其切割NK细胞的云母/ B系列配体。通过控制NK细胞MITF的黑色素瘤识别，从而控制对先天免疫系统的黑色素瘤反应。因此，当NK介导的杀伤可以有效地抑制黑色素瘤MIT流细胞，而MITF表达细胞逃避NK细胞监测。我们的研究结果揭示了MITF活性的调节如何影响抗黑色素瘤免疫应答，对应用抗黑色素瘤免疫检查的影响。

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