Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
J Cancer Res Clin Oncol. 2023 Jan;149(1):343-356. doi: 10.1007/s00432-022-04566-1. Epub 2023 Jan 3.
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.
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.
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.
The CD8 + MeTIL signature might be as a novel method to evaluate CD8 + TILs and guide immunotherapy approaches.
目前肿瘤浸润淋巴细胞（TILs），特别是 CD8+TILs 的评估方法主要依赖于具有高度变异性的半定量免疫组织化学。我们旨在构建一种基于 CD8+TIL（CD8+MeTIL）的个体化 DNA 甲基化特征，以描绘黑色素瘤免疫微环境并指导治疗选择。
分析来自癌症基因组图谱（TCGA）数据库的 457 名黑色素瘤患者的转录组谱和 DNA 甲基化数据。通过比较高 CD8+TILs 和低 CD8+TILs 组之间的差异甲基化分析，筛选差异甲基化位置（DMP）并定义 CD8+MeTIL。使用多个黑色素瘤队列研究 CD8+MeTIL 的预后价值及其对免疫治疗反应的预测价值。
我们成功构建了基于四个 DMP 的 CD8+MeTIL 特征。生存分析表明，在 TCGA-SKCM 和 GSE144487 队列中，较高的 CD8+MeTIL 评分与更差的生存结果相关。预测分析的 ROC 曲线表明，与 CD8+TILs（CIBERSORT）和 CD8B mRNA 表达相比，CD8+MeTIL 评分的生存预测更优。此外，我们发现，具有较高 CD8+MeTIL 评分的肿瘤具有免疫抑制特征，包括低免疫评分和下调的免疫相关途径。更重要的是，在两个已发表的队列中，CD8+MeTIL 评分显示出对免疫治疗获益的潜在预测价值。当将 CD8+MeTIL 与 PD-L1 表达相结合时，患者分类显示出明显不同的免疫治疗反应率和长期生存结果。
CD8+MeTIL 特征可能是评估 CD8+TILs 和指导免疫治疗方法的一种新方法。
