免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
全基因组 DNA 甲基化谱分析鉴定出一种用于黑色素瘤免疫应答的个体化预测特征
英文原题：Genome-wide DNA methylation profile analysis identifies an individualized predictive signature for melanoma immune response.
查看英文原题
Genome-wide DNA methylation profile analysis identifies an individualized predictive signature for melanoma immune response.
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研究概要
CD8 + MeTIL 特征可能作为一种评估 CD8 + TILs 和指导免疫治疗的新方法。
研究思路结论见上方概要
目的
目前对TIL（肿瘤浸润淋巴细胞）（TILs），特别是CD8 + TILs的评估方法主要依赖半定量免疫组化，变异性高。我们旨在构建一个基于DNA甲基化的个体化CD8 + TILs特征（CD8 + MeTIL），该特征可能表征黑色素瘤免疫微环境并指导治疗选择。
方法
对来自癌症基因组图谱（TCGA）数据库的457例黑色素瘤患者的转录组谱和DNA甲基化数据进行了分析。对CD8 + TIL高、低组之间进行差异甲基化分析，以筛选差异甲基化位点（DMPs）并定义CD8 + MeTIL。利用多个黑色素瘤队列研究了CD8 + MeTIL的预后价值及其对免疫治疗反应的预测价值。
结果
我们基于四个DMP成功构建了CD8 + MeTIL signature。生存分析显示，较高的CD8 + MeTIL评分与TCGA-SKCM和GSE144487队列中较差的生存结局相关。预测分析的ROC曲线显示，CD8 + MeTIL评分对生存的预测优于CD8 + TILs（CIBERSORT）和CD8B mRNA表达。此外，我们发现CD8 + MeTIL评分较高的肿瘤以免疫抑制特征为标志，包括低免疫评分和免疫相关通路下调。更重要的是，CD8 + MeTIL评分在两个已发表队列中显示出对免疫治疗获益的潜在预测价值。当将CD8 + MeTIL与PD-L1表达联合时，患者分类显示出显著不同的免疫治疗缓解率和长期生存结局。
展开英文摘要原文
PURPOSE
The current evaluation methods for tumor infiltrating lymphocytes (TILs), particularly CD8 + TILs, mainly rely on semiquantitative immunohistochemistry with high variability. We aimed to construct an individualized DNA methylation-based signature for CD8 + TILs (CD8 + MeTIL) that may characterize melanoma immune microenvironment and guide therapeutic selection.
METHODS
The transcriptome profiles and DNA methylation data of 457 melanoma patients from The Cancer Genome Atlas (TCGA) database were analyzed. Differential methylation analysis between groups with high and low CD8 + TILs was performed to select differentially methylated positions (DMPs) and define CD8 + MeTIL. The prognostic value of CD8 + MeTIL and its predictive value for immunotherapy response were investigated using multiple melanoma cohorts.
RESULTS
We successfully constructed the CD8 + MeTIL signature based on four DMPs. The survival analyses showed that higher CD8 + MeTIL score was associated with worse survival outcomes in TCGA-SKCM and GSE144487 cohorts. The ROC curve for the predictive analysis revealed that the survival prediction of CD8 + MeTIL score was superior compared with CD8 + TILs (CIBERSORT) and CD8B mRNA expression. Furthermore, we founded that tumors with higher CD8 + MeTIL score were marked with immunosuppressive characteristics, including low immune score and downregulated immune-related pathways. More importantly, the CD8 + MeTIL score showed a potential predictive value for the benefit from immunotherapy in two published cohorts. When combined CD8 + MeTIL with PD-L1 expression, the patient classification showed significantly different immunotherapy response rates and long-term survival outcomes.
CONCLUSIONS
The CD8 + MeTIL signature might be as a novel method to evaluate CD8 + TILs and guide immunotherapy approaches.
论文信息
- 作者
- Yan J、Wu X、Zhu Y、Cang S
- 第一作者单位
- Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, China.China
- 通讯作者单位
- Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, China. cangshundong@163.com.China
- 期刊
- Journal of cancer research and clinical oncology2023 Jan
- 原文标识
- PubMed 36595044 · DOI 10.1007/s00432-022-04566-1
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