Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.
Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.
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DOI：
10.1186/s12967-016-0990-x
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发表时间：
2016-08-02
影响因子：
7.4
通讯作者：
Neyns B
中科院分区：
文献类型：
--
作者：
Seremet T;Koch A;Jansen Y;Schreuer M;Wilgenhof S;Del Marmol V;Liènard D;Thielemans K;Schats K;Kockx M;Van Criekinge W;Coulie PG;De Meyer T;van Baren N;Neyns B
Ipilimumab（Ipi）改善了晚期黑色素瘤患者的生存率，在10- 15%的患者中增加了长期获益。与这种生存益处相关的肿瘤特征可以帮助优化个性化治疗策略。新鲜冷冻的黑色素瘤转移瘤从单独用Ipi（n：7）或Ipi与树突状细胞疫苗（TriMixDC-MEL）组合（n：11）治疗的患者中收集。通过免疫组织化学（IHC）、全转录组（RNA-seq）和甲基-DNA测序（MBD-seq）对样本进行分析。根据临床进展将患者分为两组：持久受益（DB; 5例患者）和无临床受益（NB; 13例患者）。通过IHC分析20个转移灶，通过RNA和MBD-seq分析12个转移灶。共鉴定出325个基因在DB和NB中差异表达。这些基因中的许多反映了体液和细胞免疫反应。MBD-seq揭示了DB和NB患者在与神经系统发育和神经元分化相关的基因甲基化方面的差异。DB肿瘤比NB肿瘤更多地被CD 8+和PD-L1+细胞浸润。B细胞（CD 20+）和巨噬细胞（CD 163+）与T细胞共定位。在几个NB样本中观察到HLA I类和TAP-1表达的局灶性缺失。黑色素瘤转移与IHC、基因表达和甲基化谱的组合分析可以潜在地鉴定对基于Ipi的免疫疗法的持久应答者。本文的在线版本（doi：10.1186/s12967-016-0990-x）包含补充材料，可供授权用户使用。
Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10–15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8+ and PD-L1+ cells than NB tumors. B cells (CD20+) and macrophages (CD163+) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy. The online version of this article (doi:10.1186/s12967-016-0990-x) contains supplementary material, which is available to authorized users.