中低剂量电离辐射对甲状腺乳头状癌免疫微环境的影响
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1.中南大学湘雅医院 普通外科,湖南 长沙 410008;2.湖南省人民医院(湖南师范大学附属第一医院) 乳甲外科,湖南 长沙 410005

作者简介:

李哲成,中南大学湘雅医院博士研究生,主要从事肝胆胰及甲状腺疾病方面的研究。

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Impact of low-to-moderate dose ionizing radiation on the immune microenvironment of papillary thyroid carcinoma
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1.Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China;2.Department of Thyroid and Breast Surgery, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha 410005, China

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    摘要:

    背景与目的 甲状腺乳头状癌(PTC)作为最常见的甲状腺癌类型,其发病率在全球范围内快速增长,对个体健康和社会公共卫生体系构成严重威胁。中低剂量电离辐射的暴露场景与普通人群的日常生活更为贴近,因而更容易引发公共卫生问题,且已经被广泛认为可能对免疫系统造成重构性影响。本研究探讨中低剂量电离辐射对PTC肿瘤免疫微环境的影响,旨在揭示这类辐射暴露事件对PTC患者的潜在危害。方法 从GEO数据库中检索并下载了包含RNA-seq数据及相应临床病例资料的两个数据集(GSE29265和GSE35570)。这两个数据集均源自因切尔诺贝利核电站事故而暴露于电离辐射的甲状腺癌患者以及散发甲状腺癌患者的样本。通过数据清洗、合并及去批次效应后,利用R语言进行差异表达基因分析、功能富集分析、免疫细胞浸润分析以及肿瘤微环境分析。结果 在肿瘤样本中,辐射暴露组相较于散发组有3个基因表达明显上调,27个基因表达明显下调。这些差异表达基因主要富集在与免疫反应密切相关的生物学功能上,包括趋化因子活动、多种免疫细胞趋化作用及肿瘤免疫等。免疫细胞浸润分析显示,在正常样本中,辐射暴露对免疫细胞浸润的影响有限;但在肿瘤样本中,辐射暴露组的免疫评分和ESTIMATE评分均明显低于散发组。进一步分析发现,辐射暴露组中总T细胞、CD4+ T细胞、CD8+ T细胞、B细胞和细胞毒性淋巴细胞在肿瘤微环境中的浸润水平明显低于散发组。结论 尽管中低剂量电离辐射对正常甲状腺组织的影响相对较小,但在PTC肿瘤微环境中,辐射暴露显著降低了多种免疫细胞亚型的浸润程度,这可能对疾病的进展产生重要影响。

    Abstract:

    Background and Aims Papillary thyroid carcinoma (PTC), the most common type of thyroid cancer, has been rapidly increasing in incidence worldwide, posing a serious threat to individual health and public healthcare systems. Exposure to low-to-moderate doses of ionizing radiation is more relevant to the daily lives of the general population and, therefore, raises greater public health concerns. It has also been widely recognized as a potential factor in immune system remodeling. This study was conducted to investigate the impact of low-to-moderate dose ionizing radiation on the tumor immune microenvironment of PTC, aiming to reveal the potential hazards of such radiation exposure in PTC patients.Methods Two datasets (GSE29265 and GSE35570) containing RNA-seq data and corresponding clinical information were retrieved and downloaded from the GEO database. These datasets included thyroid cancer samples from patients exposed to ionizing radiation due to the Chernobyl disaster, as well as sporadic thyroid cancer cases. After data cleaning, merging, batch effect correction, differential gene expression analysis, functional enrichment analysis, immune cell infiltration analysis, and tumor microenvironment analysis were performed using R language.Results In tumor samples, the radiation-exposed group exhibited significant differential gene expression compared to the sporadic group, with three genes upregulated and 27 genes downregulated. These differentially expressed genes were primarily enriched in biological functions closely related to immune responses, including chemokine activity, immune cell chemotaxis, and tumor immunity. Immune cell infiltration analysis indicated that radiation exposure had a limited impact on immune cell infiltration in normal samples. However, in tumor samples, the immune and ESTIMATE scores were significantly lower in the radiation-exposed group than in the sporadic group. Further analysis revealed that total T cells, CD4+ T cells, CD8+ T cells, B cells, and cytotoxic lymphocytes exhibited significantly lower infiltration levels in the tumor microenvironment of the radiation-exposed group than the sporadic group.Conclusion Although low-to-moderate dose ionizing radiation has a relatively minor impact on normal thyroid tissue, it significantly reduces the infiltration of various immune cell subtypes in the PTC tumor microenvironment. This reduction in immune infiltration may have important implications for disease progression.

    图1 数据集合并后样本的PCA图 A:未进行去批次效应处理的PCA图;B:去批次效应后按肿瘤/正常分组的PCA图;C:去批次效应后按辐射暴露/散发分组的PCA图Fig.1 PCA plots of the samples after dataset merging A: PCA plot without batch effect correction; B: PCA plot with batch effect correction, grouped by tumor/normal status; C: PCA plot with batch effect correction, grouped by radiation exposure/sporadic status
    图2 差异表达分析 A-B:热图分别展示了肿瘤样本和正常样本中辐射暴露组与散发组之间的差异基因表达情况;C-D:火山图分别展示了肿瘤样本和正常样本中差异表达基因的统计显著性和表达变化幅度Fig.2 Differential expression analysis A-B: Heatmaps showing the differential gene expression between the radiation-exposed and sporadic groups in tumor and normal samples, respectively; C-D: Volcano plots showing the statistical significance and expression changes of differentially expressed genes in tumor and normal samples, respectively
    图3 差异表达基因的功能富集分析 A-B:差异表达基因GO/KEGG富集分析;C-D:差异表达基因GSEA富集分析;E:差异表达基因GSVA富集分析Fig.3 Functional enrichment analysis of differentially expressed genes A-B: GO/KEGG enrichment analysis of differentially expressed genes; C-D: GSEA enrichment analysis of differentially expressed genes; E: GSVA enrichment analysis of differentially expressed genes
    图4 免疫全景图及微环境分析 A:CIBERSORT彩虹图展示了所有样本的免疫浸润全景;B:正常样本中辐射暴露组和散发组的免疫评分;C:肿瘤样本中辐射暴露组和散发组的免疫评分;D:肿瘤样本中辐射暴露组和散发组的ESTIMATE评分;E:肿瘤样本中辐射暴露组和散发组的肿瘤纯度;F:肿瘤样本中辐射暴露组和散发组的基质评分Fig.4 Immune landscape and microenvironment analysis A: CIBERSORT rainbow plot showing the immune infiltration landscape of all samples; B: Immune scores of the radiation-exposed and sporadic groups in normal samples; C: Immune scores of the radiation-exposed and sporadic groups in tumor samples; D: ESTIMATE scores of the radiation-exposed and sporadic groups in tumor samples; E: Tumor purity of the radiation-exposed and sporadic groups in tumor samples;F: Stromal scores of the radiation-exposed and sporadic groups in tumor samples
    图5 不同免疫细胞亚型的浸润水平 A-B:热图分别展示了MCPcounter和ssGSEA两种算法对辐射暴露组和散发组中的免疫细胞亚型浸润情况;C-D:MCPcounter算法分别对正常和肿瘤样本中的暴露组和散发组的免疫细胞亚型浸润情况进行对比Fig.5 Infiltration levels of different immune cell subtypes A-B: Heatmaps showing immune cell subtype infiltration in the radiation-exposed and sporadic groups based on MCPcounter and ssGSEA algorithms, respectively; C-D: Comparison of immune cell subtype infiltration between the radiation-exposed and sporadic groups in normal and tumor samples using the MCPcounter algorithm
    图6 基于ssGSEA算法对免疫细胞亚型浸润情况的分析 A:正常样本;B:肿瘤样本Fig.6 Analysis of immune cell subtype infiltration based on the ssGSEA algorithm A: Normal samples; B: Tumor samples
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李哲成,唐能,姚磊,吴昭颐,王志明.中低剂量电离辐射对甲状腺乳头状癌免疫微环境的影响[J].中国普通外科杂志,2025,34(2):346-355.
DOI:10.7659/j. issn.1005-6947.240596

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  • 收稿日期:2024-11-18
  • 最后修改日期:2025-01-11
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  • 在线发布日期: 2025-03-14