Background Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis. So far, standard systemic therapy for advanced iCCA has been a combination of gemcitabine and cisplatin. However, recent advancements in the understanding of the molecular characteristics of iCCA have opened new possibilities for molecular-targeted therapies and immunotherapy. Summary Reportedly, 9-36% of iCCA cases have an inflamed tumor immune microenvironment (TME) based on the immune gene expression signature, which is characterized by the presence of immune cells involved in anti-tumor immune responses. The majority of iCCA cases have a non-inflamed TME with a lack of effector T cells, rendering immune checkpoint inhibitors (ICIs) ineffective in these cases. Interestingly, alterations in the fibroblast growth factor receptor (FGFR2) gene and IDH1/2 gene mutations are often observed in the non-inflamed TME in iCCA. Several mechanisms have been reported for the role of driver mutations on the establishment of TME unique for iCCA. For example, IDH1/2 mutations, which cause an increase in DNA methylation, are associated with the downregulation and hypermethylation of antigen processing and presentation machinery, which may contribute to the establishment of a non-inflamed TME. Therefore, inhibitors targeting IDH1/2 may restore the DNA methylation and expression status of molecules involved in antigen presentation, potentially improving the efficacy of ICIs. FGFR inhibitors may also have the potential to modulate immunosuppressive TME by inhibitingthe suppressor of cytokine signaling 1 and activating the interferon-γ signaling as a consequence of inhibition of the FGFR signal. From this perspective, understanding the molecular characteristics of iCCA, including the TME and driver mutations, is essential for the effective application of ICIs and molecular-targeted therapies. Key Messages Combination approaches that target both the tumor and immune system hold promise for improving the outcomes of patients with iCCA. Further research and clinical trials are needed to validate these approaches and optimize the treatment strategies for iCCA.

中文翻译：

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肝内胆管癌的遗传/表观遗传改变和肿瘤免疫微环境：用分子靶向药物改变免疫微环境。


背景 肝内胆管癌（iCCA）通常在晚期才被诊断出来，导致治疗选择有限且预后不良。到目前为止，晚期 iCCA 的标准全身治疗是吉西他滨和顺铂的组合。然而，最近对 iCCA 分子特征理解的进展为分子靶向治疗和免疫治疗开辟了新的可能性。摘要 据报道，9-36% 的 iCCA 病例具有基于免疫基因表达特征的发炎的肿瘤免疫微环境 (TME)，其特征是存在参与抗肿瘤免疫反应的免疫细胞。大多数 iCCA 病例的 TME 未发炎，缺乏效应 T 细胞，导致免疫检查点抑制剂 (ICIs) 在这些病例中无效。有趣的是，在 iCCA 的非炎症 TME 中经常观察到成纤维细胞生长因子受体 (FGFR2) 基因的改变和 IDH1/2 基因突变。驱动突变在建立 iCCA 特有的 TME 过程中的作用已被报道了多种机制。例如，导致 DNA 甲基化增加的 IDH1/2 突变与抗原加工和呈递机制的下调和高甲基化有关，这可能有助于建立非炎症性 TME。因此，针对 IDH1/2 的抑制剂可能会恢复参与抗原呈递的分子的 DNA 甲基化和表达状态，从而有可能提高 ICI 的疗效。 FGFR 抑制剂还可能通过抑制细胞因子信号传导 1 的抑制剂并由于 FGFR 信号抑制而激活干扰素-γ 信号传导来调节免疫抑制性 TME。 从这个角度来看，了解 iCCA 的分子特征，包括 TME 和驱动突变，对于 ICI 和分子靶向治疗的有效应用至关重要。关键信息 针对肿瘤和免疫系统的组合方法有望改善 iCCA 患者的预后。需要进一步的研究和临床试验来验证这些方法并优化 iCCA 的治疗策略。