Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
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DOI：
10.1016/j.cell.2015.07.061
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发表时间：
2015-09-10
期刊：
影响因子：
64.5
通讯作者：
Lo RS
中科院分区：
文献类型：
--
作者：
Hugo W;Shi H;Sun L;Piva M;Song C;Kong X;Moriceau G;Hong A;Dahlman KB;Johnson DB;Sosman JA;Ribas A;Lo RS
对用于黑色素瘤的MAPK抑制剂（MAPKi）疗法的临床获得性抗性不能完全由基因组机制解释，并且可能伴随着肿瘤内免疫的共同进化。我们试图通过对治疗前和疾病进展期间活检的患者匹配的黑色素瘤肿瘤进行比较、转录组学-甲基化组学分析来发现获得性耐药和动态免疫组成的非基因组机制。耐药肿瘤中的转录组学改变与突变相比具有高度复发性，并且通常与肿瘤细胞内在CpG位点的差异甲基化相关。我们在肿瘤细胞区室中鉴定了超生理c-MET上调表达、超生理LEF 1下调表达和YAP 1特征富集作为获得性耐药的驱动因素。重要的是，在半数疾病进展性黑素瘤中，在MAPKi治疗之前的高肿瘤内细胞溶解性T细胞炎症先于CD 8 T细胞缺陷/耗竭和抗原呈递丧失，这表明对补救性抗PD-1/PD-L1免疫疗法的交叉耐药性。因此，黑色素瘤获得MAPKi抗性，具有高度动态和复发性非基因组改变和共同进化的肿瘤内免疫。
Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression, and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T-cell inflammation prior to MAPKi therapy preceded CD8 T-cell deficiency/exhaustion and loss of antigen-presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi-resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity.