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Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients

机译:黑素瘤和肿瘤免疫微环境的分子和表观遗传特征与转移患者基于ipilimumab的免疫治疗的持久缓解有关

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摘要

Background: 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. Methods: 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). Results: 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. Conclusion: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.
机译:背景:伊立木单抗(Ipilimumab,Ipi)可改善晚期黑色素瘤患者的生存率,并在10-15%的患者中增加长期获益。与此生存获益相关的肿瘤特征可能有助于优化个体化治疗策略。方法:从单独接受Ipi(n:7)或Ipi联合树突状细胞疫苗(TriMixDC-MEL)(n:11)治疗的患者中收集新鲜冷冻的黑色素瘤转移灶。通过免疫组织化学(IHC),全转录组(RNA-seq)和甲基-DNA测序(MBD-seq)对样品进行分析。结果:根据临床进展将患者分为两组:持久获益(DB; 5例)和无临床获益(NB; 13例)。 IHC分析了20个转移灶,RNA-和MBD-seq分析了12个转移灶。鉴定出325个基因在DB和NB之间差异表达。这些基因中的许多反映了体液和细胞的免疫反应。 MBD-seq揭示了DB和NB患者之间在与神经系统发育和神经元分化有关的基因甲基化方面的差异。 DB肿瘤比NB肿瘤更易被CD8(+)和PD-L1(+)细胞浸润。 B细胞(CD20(+))和巨噬细胞(CD163(+))与T细胞共定位。在几个NB样品中观察到了HLA I类和TAP-1表达的局灶性丧失。结论:将黑色素瘤转移与IHC,基因表达和甲基化分析相结合,可以潜在地识别基于Ipi的免疫治疗的持久应答者。

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