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. 2024 Jan 29;22(1):42.
doi: 10.1186/s12916-024-03257-7.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Xu Yang #  1   2 , Baofeng Lian #  3 , Nan Zhang #  1 , Junyu Long #  1 , Yiran Li  1 , Jingnan Xue  1 , Xiangqi Chen  1 , Yunchao Wang  1 , Yanyu Wang  1 , Ziyu Xun  1 , Mingjian Piao  1 , Chenpei Zhu  1 , Shanshan Wang  1 , Huishan Sun  1 , Zhijian Song  3 , Leilei Lu  3 , Xiaowei Dong  3 , Aodi Wang  3 , Wenjin Liu  3 , Jie Pan  4 , Xiaorong Hou  5 , Mei Guan  6 , Li Huo  7 , Jie Shi  8 , Haohai Zhang  9 , Jinxue Zhou  10 , Zhenhui Lu  11 , Yilei Mao  1 , Xinting Sang  1 , Liqun Wu  12 , Xiaobo Yang  13 , Kai Wang  14 , Haitao Zhao  15
Affiliations

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

Xu Yang et al. BMC Med. .

Abstract

Background: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA.

Methods: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA.

Results: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy.

Conclusions: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS.

Trial registration: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Keywords: Cholangiocarcinoma; Immune checkpoint inhibitor; Microsatellite instability-high; Overall survival; PD-1 inhibitor; PD-L1 expression; Tumor mutation burden.

PubMed Disclaimer

Conflict of interest statement

Kai Wang is an employer of OrigiMed Co., Ltd. Kai Wang, Leilei Lu, Zhijian Song and Baofeng Lian, Xiaowei Dong, Aodi Wang, and Wenjin Liu are employees of OrigiMed Co., Ltd. The other authors report no potential conflicts of interest for this work.

Figures

Fig. 1
Fig. 1
Genomic mutation landscape in cholangiocarcinoma distinguished by MSI status. A Genetic profile of significantly altered genes and associated clinicopathological characteristics of all 887 cholangiocarcinoma patients. Only the top 20 altered genes and top 10 pathways of the MSI-H group are shown. B The TMB value in the MSI-H group was significantly higher than that in the MSS group. MSI-H, microsatellite instability-high; MSS, microsatellite stability; TMB, tumor mutation burden
Fig. 2
Fig. 2
Kaplan‒Meier estimates of overall survival (A), progression-free survival (B), clinical benefit histogram (C) of 139 advanced cholangiocarcinoma patients receiving PD-1 inhibitor-based therapy stratified by MSI status. MSI-H, microsatellite instability-high; MSS, microsatellite stability
Fig. 3
Fig. 3
Kaplan–Meier curves for overall survival, progression-free survival and clinical benefit histogram of three classifications stratified according to MSI-H combined with PD-L1 CPS ≥ 5 (A–C). MSI-H, microsatellite instability-high; MSS, microsatellite stability; Mut, mutation; NDB, no durable benefit; OS, overall survival; PFS, progression-free survival; PD-L1, programmed death ligand 1; TMB, tumor mutation burden; WT, wild type
Fig. 4
Fig. 4
Factors contributing to MSI-H status. Using multivariate logistic regression, the association between pathways and clinical factors, and MSI-H status were analyzed. MSI-H: microsatellite instability-high
Fig. 5
Fig. 5
Potentially actionable alterations in MSI-H and MSS cancer based on the OncoKB database. A, B Level I of the proportions of MSI-H (100% vs. 0%) and TMB-H (100% vs. 8.7%) in MSI-H and MSS cancer. C, E Flow diagram in the upper part shows the list of translational targets for each OncoKB recommendation level in MSI-H, and the lower part presents the MSS cholangiocarcinoma. The widths of the belts indicate different frequencies for each target at every level. D, F The upper and lower pie plot shows the distribution of OncoKB levels for translational targets in patients with MSI-H or MSS cholangiocarcinoma. MSI-H, microsatellite instability-high; MSS, microsatellite stability; TMB-H, tumor mutation burden-high
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