 Tumor and Microenvironment Evolution during Immunotherapy with Nivoluma。 Cell 2017 171, 934-949.e15DOI: (10.1016/j.cell.2017.09.028) In the mirror 在这篇文章中，我们对用抗PD-1治疗的黑素瘤样本进行了广泛的免疫原性分析，观测并描述了肿瘤基因组和微环境特征在Nivolumab治疗选择压力下随着时间的推移如何变化。 在治疗中，基因组的改变符合治疗 依赖免疫编辑导致的克隆变化。 T细胞谱库分析确定T细胞克隆型与新生抗原的数量成正比，这些新生抗原在产生肿瘤应答的患者中变得不可检测。 基因表达分析揭示了抗-PD-1疗法诱导的转录和微环境改变，并鉴定出了上调的免疫检查点相关基因。这些数据对理解检查点抑制剂的作用机制以及设计未来免疫检查点阻断试验具有重要的意义。基于我们的观察，我们提出了一个在抗PD-1治疗下肿瘤和微环境进化的模型（如下图）  Graphical model depicting changes during anti-PD-1 therapy. (a) Changes in mutations and neoantigens during therapy. (b) Changes in TCR repertoire depend on exposure to prior immunotherapy. (c) Changes in immune landscape and checkpoints during therapy.    Association of Mutation Load and Clinical Outcome  (A) High mutation load (> 100 mutations as previously reported) is not associated with OS in Ipi-P patients (log-rank test; p = NS). (B) More subclonal mutations in Ipi-P patients (p = 0.08). Data are presented as median and IQR. (C) Clonal mutation load corresponds with response in Ipi-N but not Ipi-P patients. Data are presented as median and IQR. (D) High clonal mutation load is not associated with OS in Ipi-P patients (data split at median; log-rank test; p = NS). (E) Association of TCGA-determined recurrent tumor copy-number alterations and response. (F) Copy-number alterations in IFN-γ gene cluster and response. (G) Copy-number changes split at the median and determined as previously described (Davoli et al., 2017) influence outcome in the Ipi-P cohort (p = 0.0008; log-rank test) but not in the Ipi-N cohort (p = 0.49; log-rank test). (H) Change in mutation load is associated with response (p = 5.87e–5; Mann–Whitney test for CR/PR versus PD; red = Ipi-N; blue = Ipi-P). Data are presented as median and IQR. (I)Change in mutation load is associated with PFS (p < 0.001; log-rank test; data split at median). Changes in Tumor Clonal Composition after Treatment with Nivo Therapy  After 4 weeks of Nivo therapy, we observed a marked decrease in detectable mutations among patients with CR/PR and a moderate decrease in patients with SD. Clonality analysis identified that Nivo therapy affects the evolutionary landscape of tumors in patients with CR/PR, leading to the collapse of whole clonal populations, while in patients with SD, Nivo may shift the landscape in favor of specific subclones. Changes in Gene Expression following Nivo Therapy  A) Left: Analysis of ratio of DEGs and selected genes between pre- and on-therapy samples. Right: Examples of genes that change after initiation of Nivo. (B) Analysis of changes in gene expression (on-therapy compared with pre-therapy) that are altered in tumors that respond or do not respond to Nivo. (C) Graphical illustration of key pathways differentially expressed in (B). (D) Immune deconvolution of RNA-seq data comparing pre- and on-therapy samples. Data are presented as median and IQR. 用STAR METHODS进行了全面广泛的免疫基因组学分析   Detailed methods are provided in the online version of this paper and include the following: d KEY RESOURCES TABLE d CONTACT FOR REAGENT AND RESOURCE SHARING d EXPERIMENTAL MODEL AND SUBJECT DETAILS d METHOD DETAILS B Whole-Exome Sequencing B Neoantigen Analysis B Copy-Number Analysis B Tumor Clonality Analysis B RNA Sequencing B TCR b-Chain Sequencing and Analysis B Immunohistochemistry B Tumor Purity Assessment d QUANTIFICATION AND STATISTICAL ANALYSIS B Statistics and Survival Analysis d DATA AND SOFTWARE AVAILABILITY 下一只蝴蝶 |
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