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Molecular Diagnostics

Alterations in genomic features and the tumour immune microenvironment predict immunotherapy outcomes in advanced biliary tract cancer patients

British Journal of Cancer volume 132, pages 1072–1082 (2025)Cite this article

Subjects

Abstract

Background

The response to immunotherapy is limited in advanced biliary tract cancer (BTC). Response prediction is a serious challenge in the clinic.

Methods

This study included 60 patients with advanced BTC who received anti-PD-1 treatment. Among these patients, 30 were subjected to 520 gene panel sequencing, and 50 were subjected to multiplex circulating cytokine testing. The entropy and mutation features were analysed via the optimized pipeline based on our previous work. The repeated LASSO algorithm was used to identify the optimal features. The associations between sequence features and cell communications were explored by analysing single-cell transcriptome data from BTC (GSE125449). Cox regression was used to develop the integrated model. Time-dependent C-index, Kaplan‒Meier, and receiver operating characteristic (ROC) curves were used to assess the prediction performance.

Results

TP53, NRAS, FBXW7, and APC were identified as prognosis-related genes. The average C-indices of sequence entropy (0.819) and mutation (0.817) for overall survival (OS) were significantly greater than those of tumour mutation burden (TMB, 0.392) and mutation score (0.638). Single-cell transcriptome data revealed that TP53, KRAS, and NRAS were enriched in plasmacytoid dendritic cells (pDCs) and that the communication between pDCs and macrophages was mediated through the CXCL signalling pathway. The integrated model (EM-CXCL10) showed powerful predictive performance for survival status (AUC: 0.863, 95% CI: 0.643–0.972) and objective response rate (AUC: 0.990, 95% CI: 0.822–1.000).

Conclusions

This study constructed a multidimensional strategy that might indicate the prognosis of BTC immunotherapy, enabling the recognition of BTC patients who would benefit from immunotherapy, thereby guiding personalized clinical decision-making.

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Fig. 1: Association between TMB and immunotherapy outcomes in BTC patients.
Fig. 2: Genetic mutations associated with an immunotherapy response.
Fig. 3: Prognostic mutation signatures in BTC patients undergoing immunotherapy.
Fig. 4: The immune microenvironment landscape in BTC patients receiving immunotherapy.
Fig. 5: Prognostic predictive performance of EM-CXCL10 in BTC patients receiving immunotherapy.

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Data availability

Data sources and handling of the publicly available datasets used in this study are described in the Materials and Methods. Further details and other data that supports the findings of this study are available from the corresponding authors upon request.

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Funding

Innovation Group Project of Shanghai Municipal Health Commission [2019CXJQ03]; National Natural Science Foundation of China [82372321; 32370694]; Shanghai Public Health Research Project [2024GKM25]; Clinical Research Project of Shanghai Municipal Health Commission [20224Y0057].

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Author notes

  1. These authors contributed equally: Chenjun Huang, Zhiquan Qiu, Honglian Huang.

Authors and Affiliations

  1. Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China

    Chenjun Huang, Honglian Huang, Xiao Xiao, Xuewen Xu, Ying Wang & Chunfang Gao

  2. Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China

    Zhiquan Qiu & Xiaoqing Jiang

  3. School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Honglian Huang

  4. Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China

    Fei Du, Jun Ji, Ying Wang & Chunfang Gao

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Contributions

CJH, YW, and CFG contributed to the design of the work. XX, FD, JJ, XQJ and XWX were involved in the acquisition of data. Analysis was carried out by CJH, LHH, and YW, while ZQQ, and CFG handled the interpretation of data. LHH and YW developed new methods used in the work. Additionally, CJH, YW, and CFG were responsible for drafting or substantively revising the manuscript.

Corresponding authors

Correspondence to Ying Wang or Chunfang Gao.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Institutional Ethics Committee of the leading medical center (Shanghai Eastern Hepatobiliary Surgery Hospital, EHBHKY2018-02-014). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all participants.

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All authors approved the final manuscript and the submission to this journal.

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Huang, C., Qiu, Z., Huang, H. et al. Alterations in genomic features and the tumour immune microenvironment predict immunotherapy outcomes in advanced biliary tract cancer patients. Br J Cancer 132, 1072–1082 (2025). https://doi.org/10.1038/s41416-025-03011-7

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