Ni Jiaojiao, Li Chaoqun, Xu Xiaoqing, Xu Qi, Yin Qian, Chen Hanlin, Zhou Shurui, Li Jingjing, Zheng Qinhong, Xie Yanru, Hua Hongjun, Jin Jianying, Xie Tieming, Zhao Haiping, Yan Feng, Shen Junjun, Huang Yihui, Zheng Wangye, Yan Junrong, Wu Xiaoying, Wang Song, Ou Qiuxiang, Shao Yang, Wu Wei, Zhuo Wei, Ying Jieer
Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China.
Department of Oncology, Hangzhou Xixi Hospital, Hangzhou Sixth People's Hospital, Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310023, China.
BMC Med. 2025 Jul 22;23(1):435. doi: 10.1186/s12916-025-04263-z.
The limited response rates of immune checkpoint inhibitors in biliary tract cancers (BTC) highlight the need for effective biomarkers to optimize patient selection.
Baseline tumor tissues from 125 patients with advanced BTC treated with first-line chemoimmunotherapy (chemoIO) were analyzed using targeted DNA sequencing and bulk RNA sequencing. In vitro and in vivo experiments were conducted to investigate the role of identified biomarkers in BTC.
Mutations in TP53, BRCA2, cytokine genes, and high tumor mutation burden were significantly associated with treatment response. In contrast, KRAS G12D and ARID1A mutations were linked to poorer survival outcomes. High expression levels of CXCL9 and CTLA4 expression were associated with improved treatment response, prolonged progression-free survival, and overall survival. Using these biomarkers, patients were categorized into three molecular subtypes, with Type I patients demonstrating the most favorable outcomes under chemoIO. Subsequent RNA analysis revealed that elevated CXCL9 expression was associated with increased immune checkpoint expression within the tumor and heightened immune activity in the tumor microenvironment. In the mouse orthotopic cholangiocarcinoma model, CXCL9 overexpression enhanced chemoIO efficacy. Immunohistochemistry and flow cytometry showed that CXCL9 promoted T-cell infiltration and activation. In vitro experiments using multiple BTC cell lines further demonstrated that CXCL9 was essential for maintaining T cell cytotoxicity. The immune-modulatory effects of CXCL9/CTLA4 and their predictive value for treatment efficacy were further validated in a multicenter BTC cohort.
This study identified several predictive biomarkers associated with the response and efficacy of chemoIO in advanced BTC, offering valuable insights into patient stratification and refining therapeutic strategies.
免疫检查点抑制剂在胆管癌（BTC）中的缓解率有限，这凸显了需要有效的生物标志物来优化患者选择。
对125例接受一线化疗免疫疗法（化疗联合免疫治疗）的晚期BTC患者的基线肿瘤组织进行靶向DNA测序和批量RNA测序分析。进行了体外和体内实验，以研究已鉴定生物标志物在BTC中的作用。
TP53、BRCA2、细胞因子基因的突变以及高肿瘤突变负荷与治疗反应显著相关。相比之下，KRAS G12D和ARID1A突变与较差的生存结果相关。CXCL9的高表达水平和CTLA4表达与改善的治疗反应、延长的无进展生存期和总生存期相关。使用这些生物标志物，患者被分为三种分子亚型，I型患者在化疗联合免疫治疗下显示出最有利的结果。随后的RNA分析表明，CXCL9表达升高与肿瘤内免疫检查点表达增加以及肿瘤微环境中免疫活性增强相关。在小鼠原位胆管癌模型中，CXCL9过表达增强了化疗联合免疫治疗的疗效。免疫组织化学和流式细胞术显示，CXCL9促进T细胞浸润和激活。使用多种BTC细胞系进行的体外实验进一步证明，CXCL9对于维持T细胞细胞毒性至关重要。CXCL9/CTLA4的免疫调节作用及其对治疗疗效的预测价值在一个多中心BTC队列中得到了进一步验证。
本研究鉴定了几种与晚期BTC化疗联合免疫治疗的反应和疗效相关的预测生物标志物，为患者分层和完善治疗策略提供了有价值的见解。
