Lu Zhihao, Du Wenting, Jiao Xi, Wang Yanni, Shi Jingwen, Shi Yang, Shu Yongqian, Niu Zuoxing, Hara Hiroki, Wu Jun, Hsu Chih-Hung, Van Cutsem Eric, Brock Malcolm V, Zhang Zhang, Ding Ningning, Zhang Yun, Shen Zhirong, Shen Lin
Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
Clinical Biomarker, BeiGene (Shanghai) Co, Ltd, Shanghai, China.
J Clin Oncol. 2025 Jun;43(16):1898-1909. doi: 10.1200/JCO-24-01818. Epub 2025 Apr 3.
Although multiple agents targeting PD-1 have been approved as second-line treatment for esophageal squamous cell carcinoma (ESCC), only a fraction of patients derive long-term survival. Hence, reliable predictive biomarkers are urgently needed.
Comprehensive tumor genomic profiling and transcriptome sequencing were performed on samples from the RATIONALE-302 study. We also conducted single-cell RNA sequencing analysis on knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti-PD-1 benefit.
We identified mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months 5.3 months; hazard ratio, 0.35 [95% CI, 0.17 to 0.71]). At the transcriptional level, type I IFN (IFN-I)/toll-like receptor expression signatures were positively associated with OS benefit of tislelizumab, whereas B-cell and neutrophil signatures predicted unfavorable OS. Exploratory analyses showed that the presence of mutation correlated with enrichment of IFN-I signatures and reduced infiltration of B cells and neutrophils. In murine models, comparative single-cell transcriptome analyses further revealed that deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti-PD-1 treatment.
Our data provide novel insights for anti-PD-1 treatment selection using mutations and may provide a rationale for combination therapy in ESCC.
尽管多种靶向程序性死亡蛋白1（PD-1）的药物已被批准用于食管鳞状细胞癌（ESCC）的二线治疗，但只有一小部分患者能获得长期生存。因此，迫切需要可靠的预测性生物标志物。
对RATIONALE-302研究的样本进行了全面的肿瘤基因组分析和转录组测序。我们还对敲除ESCC的小鼠模型进行了单细胞RNA测序分析，以进一步探索抗PD-1获益潜在的分子机制。
我们确定了[具体突变名称]突变是替雷利珠单抗对比化疗可实现更长总生存期（OS）的潜在预测生物标志物（18.4个月对5.3个月；风险比，(0.35[95%)置信区间，(0.17)至(0.71])）。在转录水平上，I型干扰素（IFN-I）/Toll样受体表达特征与替雷利珠单抗的OS获益呈正相关，而B细胞和中性粒细胞特征则预示着OS不佳。探索性分析表明，[具体突变名称]突变的存在与IFN-I特征的富集以及B细胞和中性粒细胞浸润减少相关。在小鼠模型中，比较单细胞转录组分析进一步显示，[具体突变名称]缺陷促进了更具免疫活性的肿瘤微环境，增强了抗PD-1治疗效果。
我们的数据为利用[具体突变名称]突变进行抗PD-1治疗选择提供了新见解，并可能为ESCC的联合治疗提供理论依据。
