ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1636367
This article is part of the Research TopicIntrahepatic Cholangiocarcinoma: Emerging Insights from Pathobiology to Clinical Translation – Innovative Strategies, Challenges, and OpportunitiesView all 6 articles
Claudin18.2 Defines a Prognostically Distinct Subgroup of Intrahepatic Cholangiocarcinoma via CD8 + T-Cell Exclusion
Provisionally accepted
- 1The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- 2Huashan Hospital, Fudan University, Shanghai, China
- 3Wuxi No 5 People's Hospital, Wuxi, China
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Background and Purpose: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited therapeutic options. Claudin18.2 (CLDN18.2), a tight junction protein aberrantly expressed in gastrointestinal cancers, has not been systematically evaluated in ICC. This study investigates CLDN18.2’s expression, clinical relevance, and interplay with the tumor immune microenvironment (TIME) in ICC. Method: CLDN18.2 expression was analyzed in 83 ICC and 47 matched non-tumor tissues on tissue microarray sections using immunohistochemistry (IHC). Bioinformatics validation utilized ArrayExpress (E-MTAB-6389) and GEO (GSE119336, GSE107943, GSE89749, GSE32225) datasets. Clinicopathological correlations, survival analysis, and CD8+ tumor-infiltrating lymphocytes (TILs) quantification were performed. Results: CLDN18.2 was exclusively expressed in 24.1% (20/83) of ICC tissues, absent in non-tumor tissues. Positive CLDN18.2 expression correlated with elevated serum CA19-9 (P = 0.026), smaller tumor size (P = 0.03), unifocality (P = 0.03), and higher recurrence (P = 0.018). Multivariable analysis identified CLDN18.2 as an independent prognostic factor for reduced overall survival (OS: HR = 2.555, 95% CI = 1.250–5.223, P = 0.01) and disease-free survival (DFS: HR = 2.229, 95% CI = 1.125–4.415, P = 0.022). Single-sample gene set enrichment analysis (ssGSEA) analysis revealed an inverse correlation between CLDN18 expression and CD8+ T cells (P = 0.012), while IHC showed a trend toward negative correlation between CLDN18.2 expression and CD8+ TILs density (P = 0.12). Combined stratification showed optimal OS in CLDN18.2- /CD8high patients versus worst outcomes in CLDN18.2+ /CD8low subgroup (P = 0.006). Conclusions: CLDN18.2 is a tumor-specific prognostic biomarker in ICC, marking aggressive subsets with early recurrence. Combined CLDN18.2/CD8+ TILs stratification enhances prognostic precision and suggests synergistic potential for CLDN18.2 targeted therapies with immunomodulation. These findings warrant clinical validation to guide personalized treatment strategies.
Keywords: CLDN18.2, intrahepatic cholangiocarcinoma, prognosis, Clinicopathological features, CD8+ T-cell
Received: 28 May 2025; Accepted: 07 Aug 2025.
Copyright: © 2025 Yu, Pan, Li, Guo, Xu, Zhu and Yin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ying Zhu, Huashan Hospital, Fudan University, Shanghai, China
Baobing Yin, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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