Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no reports on tumor immune microenvironment (TIME) analyses based on iCCA subclassifications. This study investigated subclassification-specific TIMEs in iCCAs for the purpose of establishing appropriate pharmacotherapy.Methods: A total of 131 resected iCCA cases were analyzed, comprising 73 tumors classified as small-duct-type and 58 as large-duct-type based on pathological evaluation. Immunohistochemical analyses targeting CD8, PD-1, PD-L1, CTLA-4, and S100 protein (a dendritic cell [DC] marker) were performed to investigate the immune-cell status in each subclassification.Results: Large-duct-type iCCA had a significantly higher CD8 expression in tumor-infiltrating cells than small-duct-type ICC. However, the expression of other molecules did not significantly differ between the two tumor types. The proportion of tumors with a high level of S100 protein expression (DC-high group) in tumor-infiltrating cells was significantly higher in small-duct-type ICCs than in large-duct-type iCCAs (30% vs. 1.7%). In small-duct-type iCCAs, the expression levels of CD8, PD-1, PD-L1, and CTLA-4 were significantly higher in the DC-high group than in the DC-low group.Conclusions: We revealed subclassification-specific TIMEs in iCCAs. A subset of small-duct-type iCCAs exhibited strong DC infiltration. In these patients, the tumors may establish an immunosuppressive TIME to evade antitumor immunity triggered by DC-mediated antigen presentation. These findings may contribute to the development of tailored pharmacotherapy for each iCCA subclassification.
背景/目的：肝内胆管癌（iCCA）可分为小胆管型与大胆管型。小胆管型iCCA预后较好，且不同亚型需采用不同的手术策略。包括免疫检查点抑制剂在内的化疗疗效可能因亚型而异。然而，目前尚无基于iCCA亚型的肿瘤免疫微环境（TIME）分析报告。本研究旨在探究iCCA亚型特异性TIME，以建立合适的药物治疗策略。 方法：共分析131例切除的iCCA病例，根据病理评估分为73例小胆管型和58例大胆管型。通过针对CD8、PD-1、PD-L1、CTLA-4及S100蛋白（树突状细胞[DC]标志物）的免疫组化分析，探究各亚型的免疫细胞状态。 结果：大胆管型iCCA肿瘤浸润细胞中CD8表达显著高于小胆管型iCCA。然而，其他分子的表达在两种肿瘤类型间无显著差异。小胆管型iCCA中S100蛋白高表达（DC高表达组）的肿瘤比例显著高于大胆管型iCCA（30% vs. 1.7%）。在小胆管型iCCA中，DC高表达组的CD8、PD-1、PD-L1和CTLA-4表达水平均显著高于DC低表达组。 结论：本研究揭示了iCCA的亚型特异性TIME。部分小胆管型iCCA表现出强烈的DC浸润。在这些患者中，肿瘤可能通过建立免疫抑制性TIME来逃避DC介导的抗原呈递触发的抗肿瘤免疫。这些发现可能有助于针对不同iCCA亚型开发个体化药物治疗方案。
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