杨黎, 张茹, 黄建敏, 宋亚东, 张志新, 张毅. 肿瘤患者T细胞受体多样性和克隆性的高通量测序分析[J]. 中国肿瘤临床, 2023, 50(2): 55-64. DOI: 10.12354/j.issn.1000-8179.2023.20221143
引用本文: 杨黎, 张茹, 黄建敏, 宋亚东, 张志新, 张毅. 肿瘤患者T细胞受体多样性和克隆性的高通量测序分析[J]. 中国肿瘤临床, 2023, 50(2): 55-64. DOI: 10.12354/j.issn.1000-8179.2023.20221143
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Li Yang, Ru Zhang, Jianmin Huang, Yadong Song, Zhixin Zhang, Yi Zhang. High-throughput sequencing analysis of T cell receptor diversity and clonality in patients with cancer[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2023, 50(2): 55-64. DOI: 10.12354/j.issn.1000-8179.2023.20221143
Citation: Li Yang, Ru Zhang, Jianmin Huang, Yadong Song, Zhixin Zhang, Yi Zhang. High-throughput sequencing analysis of T cell receptor diversity and clonality in patients with cancer[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2023, 50(2): 55-64. DOI: 10.12354/j.issn.1000-8179.2023.20221143
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肿瘤患者T细胞受体多样性和克隆性的高通量测序分析

High-throughput sequencing analysis of T cell receptor diversity and clonality in patients with cancer

    摘要
  • 摘要:
      目的  探讨肺癌和食管癌患者外周血T细胞受体（T cell receptor，TCR）多样性和克隆分布，以及食管癌外周血和肿瘤浸润淋巴细胞中T细胞TCR的差异情况。
      方法  收集自2019年4月至2021年5月郑州大学第一附属医院未行放、化疗，并排除严重感染性疾病、自身免疫性疾病以及近期使用免疫抑制剂治疗史的8例食管癌、8例肺癌患者的外周血标本，选取其中1例食管癌患者肿瘤组织标本进行TCR测序。17例健康人外周血标本作为对照组。分析肿瘤患者与健康人之间以及早期、晚期肿瘤患者之间TCR多样性指数（D50）、VJ基因使用频率以及CDR3序列克隆型频率的差异。
      结果  食管癌、肺癌患者外周血TCR CDR3序列的D50值分别为（0.031±0.028）和（0.077±0.034），均低于健康人（0.145±0.057），P<0.000 1和P=0.005 3。食管癌、肺癌外周血TCR CDR3最大克隆比例分别为（10.640±7.640）%和（8.334±5.575）% ，均高于健康人（4.070±2.341）%， P=0.003 1和P=0.011 9。且TCR CDR3序列的最大克隆比例与D50值呈负相关。食管癌和肺癌患者早期外周血T细胞TCR多样性（D50） 分别为（0.057±0.028）和（0.106±0.007）明显高于晚期患者分别为（0.015±0.014，P=0.028 5）和（0.059±0.030，P=0.041 7）。随着疾病进展，肺癌和食管癌患者外周血TCR CDR3中TRBV和TRBJ基因组合使用减少，单个或多个TCR克隆型占比明显增高，存在明显的单一性。
      结论  肺癌和食管癌中外周血TCR谱多样性低于健康人，且存在克隆性增殖。在肿瘤发展中，TCR谱多样性降低，提示TCR谱为肿瘤的诊断、免疫评估提供了潜在的生物标志物，具有重要的临床指导意义。

     

    Abstract:
      Objective  To analyze the characteristics of the peripheral blood T cell receptor (TCR) repertoire, including diversity and clonality, in patients with esophageal cancer (EC) and lung cancer (LC), and to compare TCR repertoires between peripheral blood mononuclear cells and tumor-infiltrating lymphocytes in patients with EC.
      Methods  From April 2019 to May 2021 in The First Affiliated Hospital of Zhengzhou University, we collected peripheral blood samples from eight patients with EC and eight with LC, without radiotherapy or chemotherapy, and collected tissue from one patient with EC to perform high-throughput TCR sequencing. Patients with severe infectious diseases, autoimmune diseases, and recent treatment histories of immunosuppressants were excluded. Peripheral blood samples from 17 healthy individuals were used as the control group. The difference in TCR diversity index (D50), Vβ and Jβ gene usage frequency, and CDR3 clonotype frequency between healthy individuals and cancer patients, as well as between patients with early and advanced cancer, were analyzed, respectively .
      Results  The D50 value of TCR CDR3 transcripts in patients with EC and LC (0.031±0.028) and (0.077±0.034) was significantly lower compared to healthy individuals (0.145±0.057), P<0.000 1 and P=0.005 3. The frequency of the largest dominant clone in patients with EC and LC (10.64±7.640)% and (8.334±5.575)% was significantly higher than in healthy individuals (4.070±2.341)%, P=0.003 1 and P=0.011 9. In addition, there was a negative correlation between the D50 value of the TCR repertoire and the frequency of the largest dominant clone (P=0.000 6). The peripheral blood TCR repertoire diversity (D50) in patients with early EC (0.057 ± 0.028) and LC (0.106±0.007) was also significantly higher than in patients with advanced EC (0.015±0.014, P=0.028 5) and LC (0.059±0.030, P=0.041 7). With the progression of disease, the recombination between TRBV and TRBJ of the peripheral blood TCR repertoire in patients with EC and LC decreased, and TCR clonotypes conferred a growth advantage with significantly monoclonality.
      Conclusions  The peripheral blood TCR repertoire diversity in patients with EC and LC is lower than in healthy individuals, and patients with cancer showed a higher degree of expanded clones. Additionally, the circulating TCR repertoire diversity gradually decreases with cancer progression. TCR repertoire can reflect human immune function and also provide a potential biomarker for the diagnosis of tumors.

     

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