Yang Yong, Jiang Hui-Yu, Li Yuan, Wu Fang, Chen Zhao-Yang, Zheng Guo-Ping, Su Wen-Zhong, Wang Hai-Long, Pang Min
School of Basic Medicine, Basic Medical Science Center, Institute of Cancer Biology, Shanxi Medical University, Jinzhong, China.
Department of Pulmonary and Critical Care Medicine, The First Hospital, NHC Key Laboratory of Pneumoconiosis, Shanxi Province Key Laboratory of Respiratory Disease, Shanxi Medical University, Taiyuan, 030001, China.
BMC Cancer. 2025 Jul 1;25(1):1105. doi: 10.1186/s12885-025-14523-z.
Although there has been progress in developing T-cell receptor (TCR)-based biomarkers to predict clinical benefit (CB) in patients treated with immune checkpoint blockade (ICB) therapy, studies on the circulating TCR repertoire in non-small cell lung cancer (NSCLC) remain limited. Therefore, further investigation and validation of the TCR repertoire as a potential biomarker for predicting the benefit of immune checkpoint inhibitor therapy are needed.
Blood samples were collected from patients with advanced NSCLC before initiating anti-programmed cell death 1 (anti-PD-1) antibody treatment in combination with chemotherapy. Next-generation sequencing was used to analyze the complementarity-determining region 3 (CDR3) of the T cell receptor beta (TRB)gene. Richness, Shannon diversity indices, and the usage of variable and joining genes were studied. TCR repertoire metrics were then correlated with CB, progression-free survival (PFS), and overall survival (OS).
We found that the number of unique clones and richness index were comparable between the clinical benefit (CB) and no-clinical benefit (non-CB) groups. A high number of unique clones and a higher richness index were correlated with clinical benefit among patients treated with chemoimmunotherapy (ChIO) therapy. However, despite this association, a statistically non-significant correlation was observed between any of the TCR repertoire metrics and PFS or OS in patients treated with ChIO. Higher TRBJ2-1 frequencies were associated with clinical benefit. Most clonotypes contained CDR3 fragments ranging from 12 to 16 amino acids in length. However, visualization of the relative similarity of TCR repertoires using multidimensional scaling analysis revealed that TCR repertoires of the benefit group could not be separated from those of the benefit group.
The circulating TCR repertoire may serve as a potential tool for predicting clinical outcomes of anti-PD-1 plus chemotherapy, aiding the selection of patients likely to experience clinical benefit. Further large-scale prospective studies are required to validate these findings.
The online version contains supplementary material available at 10.1186/s12885-025-14523-z.
尽管在开发基于T细胞受体（TCR）的生物标志物以预测接受免疫检查点阻断（ICB）治疗患者的临床获益（CB）方面已取得进展，但关于非小细胞肺癌（NSCLC）循环TCR库的研究仍然有限。因此，需要进一步研究和验证TCR库作为预测免疫检查点抑制剂治疗获益的潜在生物标志物。
在晚期NSCLC患者开始接受抗程序性细胞死亡蛋白1（anti-PD-1）抗体联合化疗之前采集血样。采用下一代测序分析T细胞受体β（TRB）基因的互补决定区3（CDR3）。研究了丰富度、香农多样性指数以及可变基因和连接基因的使用情况。然后将TCR库指标与临床获益、无进展生存期（PFS）和总生存期（OS）进行关联分析。
我们发现，临床获益（CB）组和无临床获益（非CB）组之间的独特克隆数和丰富度指数相当。在接受化疗免疫治疗（ChIO）的患者中，大量独特克隆和较高的丰富度指数与临床获益相关。然而，尽管存在这种关联，但在接受ChIO治疗的患者中，任何TCR库指标与PFS或OS之间均未观察到具有统计学意义的相关性。较高的TRBJ2-1频率与临床获益相关。大多数克隆型包含长度为12至16个氨基酸的CDR3片段。然而，使用多维尺度分析对TCR库的相对相似性进行可视化显示，获益组的TCR库与获益组的TCR库无法区分开来。
循环TCR库可能作为预测抗PD-1加化疗临床结局的潜在工具，有助于选择可能从临床中获益的患者。需要进一步开展大规模前瞻性研究来验证这些发现。
在线版本包含可在10.1186/s12885-025-14523-z获取的补充材料。
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