定量蛋白质组分析揭示了结直肠癌外周免疫系统的功能性改变。

IF 6.1 2区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Molecular & Cellular Proteomics Pub Date : 2024-06-01 Epub Date: 2024-05-11 DOI:10.1016/j.mcpro.2024.100784
Wenyuan Zhu, Minzhe Li, Qingsong Wang, Jian Shen, Jianguo Ji
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引用次数: 0

摘要

结直肠癌(CRC)的特点是发病率高、死亡率高以及对免疫疗法的反应有限。外周免疫系统是肿瘤免疫的重要组成部分,增强外周免疫有助于抑制肿瘤进展。然而,CRC 周围免疫系统的功能改变尚不清楚。在这里,我们利用基于质谱的定量蛋白质组学建立了 CRC 周围免疫系统的蛋白质表达图谱,包括血浆和五种免疫细胞(CD4+ T 细胞、CD8+ T 细胞、单核细胞、自然杀伤细胞和 B 细胞)。综合多维分析的结果,我们观察到 CRC 的炎症表型增强,包括血浆炎症蛋白表达升高、单核细胞炎症通路激活以及与炎症相关的配体-受体相互作用增加。值得注意的是,我们观察到肿瘤对外周 T 细胞的影响,包括细胞亚群比例的改变和细胞功能的抑制。对 CD4+ T 细胞功能的抑制主要是由蛋白酪氨酸磷酸酶的高表达水平介导的。其中,蛋白酪氨酸磷酸酶受体 J 型(PTPRJ)的表达随着 CRC 的进展而逐渐升高;体外敲除 PTPRJ 可促进 T 细胞活化,从而增强外周免疫力。我们还发现,富亮氨酸α-2糖蛋白1(LRG1)和脂蛋白A4(APOA4)的组合对结直肠癌的预测能力最强,有望成为一种生物标志物。总之,这项研究提供了对 CRC 周围免疫系统的全面了解。它还提供了有关这些外周免疫特征作为诊断指标和治疗靶点的潜在临床用途的见解。
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Quantitative Proteomic Analysis Reveals Functional Alterations of the Peripheral Immune System in Colorectal Cancer.

Colorectal cancer (CRC) is characterized by high morbidity, high mortality, and limited response to immunotherapies. The peripheral immune system is an important component of tumor immunity, and enhancements of peripheral immunity help to suppress tumor progression. However, the functional alterations of the peripheral immune system in CRC are unclear. Here, we used mass spectrometry-based quantitative proteomics to establish a protein expression atlas for the peripheral immune system in CRC, including plasma and five types of immune cells (CD4+ T cells, CD8+ T cells, monocytes, natural killer cells, and B cells). Synthesizing the results of the multidimensional analysis, we observed an enhanced inflammatory phenotype in CRC, including elevated expression of plasma inflammatory proteins, activation of the inflammatory pathway in monocytes, and increased inflammation-related ligand-receptor interactions. Notably, we observed tumor effects on peripheral T cells, including altered cell subpopulation ratios and suppression of cell function. Suppression of CD4+ T cell function is mainly mediated by high expression levels of protein tyrosine phosphatases. Among them, the expression of protein tyrosine phosphatase receptor type J (PTPRJ) gradually increased with CRC progression; knockdown of PTPRJ in vitro could promote T cell activation, thereby enhancing peripheral immunity. We also found that the combination of leucine-rich α-2 glycoprotein 1 (LRG1) and apolipoprotein A4 (APOA4) had the best predictive ability for colorectal cancer and has the potential to be a biomarker. Overall, this study provides a comprehensive understanding of the peripheral immune system in CRC. It also offers insights regarding the potential clinical utilities of these peripheral immune characteristics as diagnostic indicators and therapeutic targets.

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来源期刊
Molecular & Cellular Proteomics
Molecular & Cellular Proteomics 生物-生化研究方法
CiteScore
11.50
自引率
4.30%
发文量
131
审稿时长
84 days
期刊介绍: The mission of MCP is to foster the development and applications of proteomics in both basic and translational research. MCP will publish manuscripts that report significant new biological or clinical discoveries underpinned by proteomic observations across all kingdoms of life. Manuscripts must define the biological roles played by the proteins investigated or their mechanisms of action. The journal also emphasizes articles that describe innovative new computational methods and technological advancements that will enable future discoveries. Manuscripts describing such approaches do not have to include a solution to a biological problem, but must demonstrate that the technology works as described, is reproducible and is appropriate to uncover yet unknown protein/proteome function or properties using relevant model systems or publicly available data. Scope: -Fundamental studies in biology, including integrative "omics" studies, that provide mechanistic insights -Novel experimental and computational technologies -Proteogenomic data integration and analysis that enable greater understanding of physiology and disease processes -Pathway and network analyses of signaling that focus on the roles of post-translational modifications -Studies of proteome dynamics and quality controls, and their roles in disease -Studies of evolutionary processes effecting proteome dynamics, quality and regulation -Chemical proteomics, including mechanisms of drug action -Proteomics of the immune system and antigen presentation/recognition -Microbiome proteomics, host-microbe and host-pathogen interactions, and their roles in health and disease -Clinical and translational studies of human diseases -Metabolomics to understand functional connections between genes, proteins and phenotypes
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