• Xu Yang, Baofeng Lian, Nan Zhang, Junyu Long, Yiran Li, Jingnan Xue, Xiangqi Chen, Yunchao Wang, Yanyu Wang, Ziyu Xun, Mingjian Piao, Chenpei Zhu, Shanshan Wang, Huishan Sun, Zhijian Song, Leilei Lu, Xiaowei Dong, Aodi Wang, Wenjin Liu, Jie Pan, Xiaorong Hou, Mei Guan, Li Huo, Jie Shi, Haohai Zhang, Jinxue Zhou, Zhenhui Lu, Yilei Mao, Xinting Sang, Liqun Wu, Xiaobo Yang, Kai Wang, and Haitao Zhao.
• Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
• Bmc Med. 2024 Jan 29; 22 (1): 4242.

BackgroundMicrosatellite 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.MethodsWe 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.ResultsDifferential 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.ConclusionsMSI-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 RegistrationThis study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).© 2024. The Author(s).

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