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Background <p>The limited response rates of immune checkpoint inhibitors in biliary tract cancers (BTC) highlight the need for effective biomarkers to optimize patient selection.</p> Methods <p>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.</p> Results <p>Mutations in <i>TP53</i>, <i>BRCA2</i>, cytokine genes, and high tumor mutation burden were significantly associated with treatment response. In contrast, <i>KRAS</i> G12D and <i>ARID1A</i> mutations were linked to poorer survival outcomes. High expression levels of <i>CXCL9</i> and <i>CTLA4</i> 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 <i>CXCL9</i> 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.</p> Conclusions <p>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.</p>

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Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of chemoimmunotherapy in advanced unresectable biliary tract cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • Jiaojiao Ni,
  • Chaoqun Li,
  • Xiaoqing Xu,
  • Qi Xu,
  • Qian Yin,
  • Hanlin Chen,
  • Shurui Zhou,
  • Jingjing Li,
  • Qinhong Zheng,
  • Yanru Xie,
  • Hongjun Hua,
  • Jianying Jin,
  • Tieming Xie,
  • Haiping Zhao,
  • Feng Yan,
  • Junjun Shen,
  • Yihui Huang,
  • Wangye Zheng,
  • Junrong Yan,
  • Xiaoying Wu,
  • Song Wang,
  • Qiuxiang Ou,
  • Yang Shao,
  • Wei Wu,
  • Wei Zhuo,
  • Jieer Ying

摘要

Background

The limited response rates of immune checkpoint inhibitors in biliary tract cancers (BTC) highlight the need for effective biomarkers to optimize patient selection.

Methods

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.

Results

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.

Conclusions

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.