PO.CL01.05 · 临床研究
纵向液体活检鉴定头颈部鳞状细胞癌免疫检查点阻断应答的早期预测性生物标志物
Longitudinal liquid biopsy identifies an early predictive biomarker of immune checkpoint blockade response in head and neck squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
免疫检查点抑制（ICI）已成为头颈部鳞状细胞癌（HNSCC）的关键疗法，然而指导其临床应用的预测性生物标志物的开发明显滞后。当前的生物标志物如肿瘤突变负荷和PD-L1未能捕捉到可能更好地反映宿主免疫适能和驱动持久肿瘤控制的协调免疫应答的全身免疫动态。我们假设治疗诱导的循环免疫库早期变化可提供ICI应答性的动态、无创读数。我们在小鼠HNSCC模型中采用时间分辨的多组学方法，在明确的治疗前和治疗中时间点表征了对抗PD-1的外周免疫应答。单细胞转录组学和配对T/B细胞受体分析揭示，应答者中效应记忆T和B细胞库出现早期而强劲但短暂的扩增，先于肿瘤消退。效应T和B细胞丰度、克隆性和基因表达的时间变化强烈预测免疫治疗应答，其中治疗中早期时间点成为评估治疗应答的最佳窗口。这些动态免疫特征形成了一个复合转录特征——免疫肿瘤学液体生物标志物（LiBIO），源自效应T和B细胞程序，能在独立的人类HNSCC队列中准确预测ICI应答，并优于当代生物标志物如PD-L1联合阳性评分和肿瘤突变负荷。LiBIO无需重新训练即可进一步推广至黑色素瘤、非小细胞肺癌和乳腺癌，提示早期外周免疫动态捕捉到跨癌种有效抗肿瘤免疫的保守特征。总之，这些发现支持以下前提：在肿瘤引流淋巴管中区域性启动的抗肿瘤免疫应答，产生先于原发肿瘤成功控制的短暂、刻板的外周免疫应答，且外周免疫事件可作为液体生物标志物发现的基础。这一创新方法代表了从静态、以肿瘤为中心的生物标志物向宿主免疫动态监测的范式转变，能够在免疫激活的关键早期窗口实现实时治疗调整。
查看英文原文 English abstract
Immune checkpoint inhibition (ICI) has emerged as a pivotal therapy for head and neck squamous cell carcinoma (HNSCC), yet the development of predictive biomarkers to guide its clinical application has significantly lagged. Current biomarkers such as tumor mutational burden and PD-L1 fail to capture systemic immune dynamics that may better reflect host immune fitness and the coordinated immune response driving durable tumor control. We hypothesized that early treatment-induced changes in circulating immune repertoires could provide a dynamic, non-invasive readout of ICI responsiveness. Using a time-resolved, multi-omic approach in a murine HNSCC model, we characterized peripheral immune responses to anti-PD-1 across defined pre- and on-treatment timepoints. Single-cell transcriptomics and paired T/B cell receptor analyses revealed an early and robust, but transient, expansion of effector memory T and B cell repertoires in responders, preceding tumor regression. Temporal changes in effector T and B cell abundance, clonality, and gene expression strongly predicted immunotherapy response, with early on-treatment timepoints emerging as the optimal window for assessing treatment response. These dynamic immune features informed a composite transcriptional signature, Liquid Biomarker for Immuno-Oncology (LiBIO), derived from effector T and B cell programs that accurately predicts ICI response in independent human HNSCC cohorts and outperforms contemporary biomarkers such as PD-L1 combined positive score and tumor mutational burden. LiBIO further generalizes to melanoma, non-small cell lung cancer, and breast cancer without retraining, suggesting that early peripheral immune dynamics capture conserved features of effective antitumor immunity across cancer types. Collectively, these findings support the premise that antitumor immune responses initiated regionally in tumor-draining lymphatics give rise to transient, stereotyped peripheral immune responses that precede successful primary tumor control, and that peripheral immune events can serve as a foundation for liquid biomarker discovery. This innovative approach represents a paradigm shift from static, tumor-centric biomarkers to dynamic monitoring of host immunity, enabling real-time treatment adaptation during the critical early window of immune activation.
利益披露 Disclosure
R. Saddawi-Konefka, None..
L. M. Clubb, None..
C. Tang, None.