Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.
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DOI：
10.1016/j.cell.2016.02.065
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发表时间：
2016-03-24
期刊：
影响因子：
64.5
通讯作者：
Lo RS
中科院分区：
文献类型：
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作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
PD-1免疫检查点阻断为黑色素瘤患者提供了显著的临床益处。我们分析了治疗前黑色素瘤活检的体细胞突变组和转录组，以确定可能影响抗PD-1治疗的先天敏感性或耐药性的因素。我们发现，虽然总体高突变负荷与应答和无应答患者的生存率提高相关，但应答肿瘤特异性富集DNA修复基因BRCA 2的突变。先天性耐药肿瘤显示出转录特征（称为IPRES或先天抗PD-1耐药），表明参与间充质转化、细胞粘附、ECM重塑、血管生成和伤口愈合调节的基因同时上调表达。值得注意的是，MAPK靶向疗法（MAPKi）在黑色素瘤中诱导类似的特征，表明MAPKi抗性的非基因组形式介导对抗PD-1疗法的交叉抗性。在其他独立肿瘤队列中验证IPRES定义了不同类型晚期癌症的转录组亚组。这些发现表明，减弱IPRES基础的生物学过程可能会改善黑色素瘤和其他癌症类型的抗PD 1反应。
PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that, while overall high mutational loads associate with improved survival both in responding and non-responding patients, responding tumors are specifically enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES or Innate anti-PD-1 Resistance) indicating concurrent upexpression of genes involved in the regulation of mesenchymal transition, cell adhesion, ECM remodeling, angiogenesis and wound-healing. Notably, MAPK-targeted therapy (MAPKi) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPKi resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD1 response in melanoma and other cancer types.