西妥昔单抗治疗头颈部鳞状细胞癌患者的反应与外周血和肿瘤浸润 T 细胞克隆扩增特征相关，这些 T 细胞具有高 T 细胞受体克隆型。
Cetuximab Responses in Patients with HNSCC Correlate to Clonal Expansion Feature of Peripheral and Tumor-Infiltrating T Cells with Top T-Cell Receptor Clonotypes.
机构信息
UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
UPMC Hillman Cancer Center, Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
出版信息
Clin Cancer Res. 2023 Feb 1;29(3):647-658. doi: 10.1158/1078-0432.CCR-22-2355.
PURPOSE
Cetuximab is a standard-of-care treatment for head and neck squamous cell carcinoma (HNSCC). Well-defined correlative markers of therapeutic responses are still lacking. Characterizing dynamic changes of T-cell receptor (TCR) repertoire in peripheral blood and tumor tissue may facilitate developing markers for cetuximab response in HNSCCs.
EXPERIMENTAL DESIGN
We analyzed high-throughput TCRβ sequencing data generated with ImmunoSEQ platform using peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) from patients with HNSCC before and after cetuximab treatment (pre-/post-PBMC vs. pre-/post-TIL). Multiple analytic approaches were employed to normalize sequencing data.
RESULTS
Normalized TCR richness was significantly lower in post-TIL than pre-TIL, suggesting that cetuximab reduced TCR diversity and promoted TCR expansion in TIL samples, regardless of response status. The magnitude of clonal expansion (defined as expansion rate) in top 20 TCR clonotypes was significantly higher in responder PBMC with or without normalization, and in responder TIL upon normalization, than nonresponder ones. Notably, the expanded top 20 or top 50 TCR clonotypes overlapped between PBMC and TIL samples, which occurred significantly more frequently in responders than nonresponders.
CONCLUSIONS
Patients with cetuximab-treated HNSCC harbor dynamic changes of TCR repertoires correlative to therapeutic responses. The expansion rate of top TCR clonotypes in peripheral blood may serve as a minimally invasive, readily accessible, and feasible marker for predicting cetuximab responses in HNSCCs and beyond, and the expansion rate of top TCR clonotypes in TILs and their overlapping probability between PBMC and TIL may serve as additional predictive markers. Our study also highlights the importance of data normalization for TCR repertoire analysis.
目的
西妥昔单抗是头颈部鳞状细胞癌（HNSCC）的标准治疗方法。目前仍缺乏明确的治疗反应相关标志物。对患者外周血和肿瘤组织中 T 细胞受体（TCR）库的动态变化进行特征描述，可能有助于开发 HNSCC 中针对西妥昔单抗反应的标志物。
实验设计
我们分析了 HNSCC 患者在接受西妥昔单抗治疗前后（预处理 PBMC 与预处理 TIL 相比，后处理 PBMC 与后处理 TIL）的外周血单核细胞（PBMC）和肿瘤浸润淋巴细胞（TIL）的 ImmunoSEQ 平台生成的高通量 TCRβ 测序数据。采用多种分析方法对测序数据进行归一化处理。
结果
与预处理 TIL 相比，后处理 TIL 的 TCR 丰富度显著降低，提示西妥昔单抗降低了 TIL 样本中的 TCR 多样性并促进了 TCR 扩增，而与反应状态无关。在未归一化的情况下， responder PBMC 和经归一化处理的 responder TIL 中，top 20 TCR 克隆型的克隆扩增（定义为扩增率）幅度显著高于非 responder 样本。值得注意的是，在 responder PBMC 和 TIL 样本中，扩增的 top 20 或 top 50 TCR 克隆型之间存在重叠，而在 responder 样本中发生的频率显著高于非 responder 样本。
结论
接受西妥昔单抗治疗的 HNSCC 患者的 TCR 库存在与治疗反应相关的动态变化。外周血中 top TCR 克隆型的扩增率可能作为一种微创、易于获得且可行的标志物，用于预测 HNSCC 及其他疾病中对西妥昔单抗的反应，而 TIL 中 top TCR 克隆型的扩增率及其在 PBMC 和 TIL 之间的重叠概率可能作为额外的预测标志物。我们的研究还强调了 TCR 谱分析中数据归一化的重要性。
Zotero 插件