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基于三阴性乳腺癌患者中与耗竭性CD8 + T细胞相关的四个基因构建预后模型:整合单细胞RNA测序和批量RNA测序的综合分析

Development of a prognostic model based on four genes related to exhausted CD8+ T cell in triple-negative breast cancer patients: a comprehensive analysis integrating scRNA-seq and bulk RNA-seq.

作者信息

Shi Yulin, Yu Yang, Zhao Jiahan, Huang Linan, Wang Qingyang, Sun Qi, Liu Lijuan, Sun Changgang

机构信息

College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.

State Key Laboratory of Quality Research in Chinese Medicine, and Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China.

出版信息

Discov Oncol. 2025 Feb 3;16(1):114. doi: 10.1007/s12672-025-01812-z.

Abstract

Low immune infiltration is closely associated with poor clinical results and an unfavorable response to therapy in triple-negative breast cancer (TNBC). T-cell exhaustion (TEX) is a significant risk factor for tumor immunosuppression and invasion. Although improving TEX and enhancing effector function are promising strategies for strengthening immunotherapy, their role in the pathogenesis of TNBC remains unclear. This study's objective was to develop a prognostic model for TNBC based on exhausted CD8+ T-cell (CD8+ Tex)-related differentially expressed genes (DEGs) and to investigate its clinical and immune relevance. Initially, 398 CD8+ Tex-related genes were screened utilizing single-cell RNA sequencing (scRNA-seq) data from TNBC patients. Pseudotime analysis confirmed that CD8+ Tex mainly clustered at the end of the differentiation pathways, making them a critical subset in TNBC progression. By analyzing the TCGA cohort, ten CD8+ Tex-related DEGs were identified as significantly correlated with overall survival (OS) in TNBC patients, and a prognostic model containing four biomarkers (GBP1, CTSD, ABHD14B, and HLA-A) was constructed. The model demonstrated robust predictive capability in both the TCGA cohort and an external cohort, with the low-risk group exhibiting elevated expression of immunological checkpoint molecules and immune cell infiltration, as well as better responses to immunotherapy and chemotherapy. Furthermore, these four biomarkers were found to be highly expressed on CD8+ Tex and were associated with cellular communication efficiency. Therefore, this model is expected to be a new method for forecasting TNBC patients' prognosis and effectiveness of treatment, providing new insights for clinical decision-making.

摘要

低免疫浸润与三阴性乳腺癌(TNBC)的不良临床结果及对治疗的不良反应密切相关。T细胞耗竭(TEX)是肿瘤免疫抑制和侵袭的一个重要危险因素。尽管改善TEX并增强效应功能是加强免疫治疗的有前景的策略,但其在TNBC发病机制中的作用仍不清楚。本研究的目的是基于耗竭的CD8+ T细胞(CD8+ Tex)相关差异表达基因(DEG)建立TNBC的预后模型,并研究其临床和免疫相关性。最初,利用TNBC患者的单细胞RNA测序(scRNA-seq)数据筛选出398个CD8+ Tex相关基因。拟时间分析证实CD8+ Tex主要聚集在分化途径的末端,使其成为TNBC进展中的一个关键亚群。通过分析TCGA队列,确定了10个与TNBC患者总生存期(OS)显著相关的CD8+ Tex相关DEG,并构建了一个包含四个生物标志物(GBP1、CTSD、ABHD14B和HLA-A)的预后模型。该模型在TCGA队列和一个外部队列中均显示出强大的预测能力,低风险组表现出免疫检查点分子表达升高、免疫细胞浸润增加,以及对免疫治疗和化疗的更好反应。此外,发现这四个生物标志物在CD8+ Tex上高表达,并与细胞通讯效率相关。因此,该模型有望成为预测TNBC患者预后和治疗效果的新方法,为临床决策提供新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1be5/11790537/d62c56105be7/12672_2025_1812_Fig1_HTML.jpg

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