CD8+ T细胞浸润驱动的胃癌预后特征:桥接肿瘤免疫和临床结果

Yiting Qian, Bo Sun, Linying Lai, Fengying Xu, Ruilin Liu, Wenzhuo Yang
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引用次数: 0

摘要

背景:CD8+ T细胞在抗肿瘤免疫中起关键作用,其浸润水平通常与良好的预后相关。然而,胃癌(GC)肿瘤微环境(TME)中CD8+ T细胞亚群的功能异质性-特别是它们对肿瘤进展、免疫治疗反应和临床结果的不同影响-仍然缺乏特征。方法:我们将来自23个GC组织(GEO: GSE150290)的单细胞RNA测序(scRNA-seq)数据与TCGA-STAD的大量转录组学数据相结合,分析CD8+ T细胞的异质性。分析管道包括无监督聚类、伪时间轨迹分析和蛋白质-蛋白质相互作用(PPI)网络构建,以识别生存相关的中心基因。进行差异基因表达、功能富集和实验验证以确认临床相关性。结果:scRNA-seq将CD8+ T细胞分为五个功能不同的亚群:naïve/记忆亚群、衰竭亚群和三个细胞毒性亚群。其中,细胞毒性CD8+ T1细胞表现出最强的预后相关性,在g2级肿瘤中,高浸润与生存率的提高和富集相关。伪时间分析揭示了从naïve到耗尽亚群的分化轨迹,伴随着代谢和免疫检查点途径的改变。PPI网络分析发现,SELL、CD79B和RAMP2是枢纽基因,它们都与生存显著相关,并且在肿瘤分级/分期中表达差异。实验验证证实,SELL、CD79B和RAMP2敲低抑制了GC细胞的增殖,强调了它们的功能作用。结论:我们的研究揭示了GC中CD8+ T细胞的异质性,并提出了一个具有双重预后和治疗潜力的三基因标记(SELL/CD79B/RAMP2)。这些发现为分层患者、定制免疫治疗方案和开发新的靶点来增强胃癌的抗肿瘤免疫提供了可行的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A CD8+ T Cell Infiltration–Driven Prognostic Signature for Gastric Cancer: Bridging Tumor Immunity and Clinical Outcomes

A CD8+ T Cell Infiltration–Driven Prognostic Signature for Gastric Cancer: Bridging Tumor Immunity and Clinical Outcomes

A CD8+ T Cell Infiltration–Driven Prognostic Signature for Gastric Cancer: Bridging Tumor Immunity and Clinical Outcomes

Background: CD8+ T cells play pivotal roles in antitumor immunity, where infiltration levels often correlate with favorable prognosis. However, the functional heterogeneity of CD8+ T cell subsets within the gastric cancer (GC) tumor microenvironment (TME)—particularly their divergent impacts on tumor progression, immunotherapy response, and clinical outcomes—remains poorly characterized.

Methods: We integrated single-cell RNA sequencing (scRNA-seq) data from 23 GC tissues (GEO: GSE150290) with bulk transcriptomic profiles from TCGA-STAD to dissect CD8+ T cell heterogeneity. Analytical pipelines included unsupervised clustering, pseudotime trajectory analysis, and protein–protein interaction (PPI) network construction to identify survival-associated hub genes. Differential gene expression, functional enrichment, and experimental validation were performed to confirm clinical relevance.

Results: scRNA-seq resolved CD8+ T cells into five functionally distinct subsets: naïve/memory, exhausted, and three cytotoxic subpopulations. Among these, cytotoxic CD8+ T1 cells exhibited the strongest prognostic relevance, with high infiltration correlating to improved survival and enrichment in G2-grade tumors. Pseudotime analysis revealed differentiation trajectories from naïve to exhausted subsets, accompanied by metabolic and immune checkpoint pathway alterations. PPI network analysis identified SELL, CD79B, and RAMP2 as hub genes, all significantly linked to survival and differentially expressed across tumor grades/stages. Experimental validation confirmed that SELL, CD79B, and RAMP2 knockdown suppressed GC cell proliferation, underscoring their functional roles.

Conclusion: Our study unveils the landscape of CD8+ T cell heterogeneity in GC and proposes a three-gene signature (SELL/CD79B/RAMP2) with dual prognostic and therapeutic potential. These findings provide actionable insights for stratifying patients, tailoring immunotherapy regimens, and developing novel targets to enhance antitumor immunity in GC.

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Comparative and Functional Genomics
Comparative and Functional Genomics 生物-生化与分子生物学
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