破解脊索瘤难题:免疫检查点提供了一种潜在方式。

Cracking Chordoma's Conundrum: Immune Checkpoints Provide a Potential Modality.

作者信息

Liu Weihai, Regmi Moksada, Chen Xiaodong, Liu Shikun, Xiong Ying, Dai Yuwei, Wang Yingjie, Yang Jun, Yang Chenlong

机构信息

State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing 100191, China.

Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing 100191, China.

出版信息

Int J Med Sci. 2025 Apr 22;22(10):2318-2332. doi: 10.7150/ijms.109721. eCollection 2025.

Abstract

Chordoma, a rare malignant tumor, is notably resistant to conventional treatments including chemotherapy, radiotherapy, and targeted approaches. Immunotherapy, successful in treating other cancer types, presents a promising avenue. However, the immune microenvironment of chordoma is poorly understood, highlighting the need to investigate immune checkpoints and their potential as therapeutic targets in this context. We performed an integrated analysis of chordoma using public datasets (GSE224776, GSE56183, GSE239531) and our RNA-seq data (11 samples). Differential expression analysis (limma), gene set enrichment analysis (GSEA, clusterProfiler), immune cell infiltration assessment (ESTIMATE, immunedeconv), weighted gene co-expression network analysis (WGCNA), consensus clustering, and machine learning were employed to identify key immune-related gene modules, immunogenic subtypes, and central immune regulators. Hierarchical clustering and principal component analysis segregated chordoma from control samples post quality control. Differential expression analysis identified 2825 upregulated and 1693 downregulated genes, with significant upregulation of immune checkpoints, including PD-1 and CTLA-4. GSEA highlighted enhanced immune-related processes, particularly inflammatory responses, antigen presentation, and immune cell activation. Immune cell deconvolution demonstrated selective enrichment of memory T cells and macrophages, alongside downregulation of neutrophils and decreased effector cell scores. Consensus clustering identified a highly immunogenic chordoma subtype (Cluster 1), and WGCNA and machine learning converged on CCR7 as a central immune regulator, with core T cell-associated genes correlating with immune cell distribution patterns. This study characterizes the chordoma immune landscape, highlighting elevated immune checkpoints, distinct immunogenic subtypes, and a T cell-centered regulatory network. These findings support immune checkpoint inhibitors and other immunotherapies as promising treatments.

摘要

脊索瘤是一种罕见的恶性肿瘤,对包括化疗、放疗和靶向治疗在内的传统治疗方法具有显著抗性。免疫疗法在治疗其他癌症类型方面取得了成功,为脊索瘤的治疗提供了一条有前景的途径。然而,人们对脊索瘤的免疫微环境了解甚少,这凸显了在此背景下研究免疫检查点及其作为治疗靶点的潜力的必要性。我们使用公共数据集(GSE224776、GSE56183、GSE239531)和我们自己的RNA测序数据(11个样本)对脊索瘤进行了综合分析。采用差异表达分析(limma)、基因集富集分析(GSEA,clusterProfiler)、免疫细胞浸润评估(ESTIMATE,immunedeconv)、加权基因共表达网络分析(WGCNA)、共识聚类和机器学习来识别关键的免疫相关基因模块、免疫原性亚型和核心免疫调节因子。在质量控制后,层次聚类和主成分分析将脊索瘤样本与对照样本区分开来。差异表达分析确定了2825个上调基因和1693个下调基因,免疫检查点包括PD-1和CTLA-4显著上调。GSEA突出了增强的免疫相关过程,特别是炎症反应、抗原呈递和免疫细胞激活。免疫细胞反卷积显示记忆T细胞和巨噬细胞选择性富集,同时中性粒细胞下调,效应细胞评分降低。共识聚类确定了一种高度免疫原性的脊索瘤亚型(簇1),WGCNA和机器学习一致认为CCR7是核心免疫调节因子,核心T细胞相关基因与免疫细胞分布模式相关。这项研究描绘了脊索瘤的免疫格局,突出了免疫检查点升高、不同的免疫原性亚型以及以T细胞为中心的调节网络。这些发现支持免疫检查点抑制剂和其他免疫疗法作为有前景的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ef66/12080586/e0f7c8aaebe3/ijmsv22p2318g001.jpg

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