Zhu Chunbin, Ma Jiaqiang, Zhu Kai, Yu Lei, Zheng Bohao, Rao Dongning, Zhang Shu, Dong Liangqing, Gao Qiang, Zhang Xiaoming, Xie Diyang
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China.
The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
JHEP Rep. 2023 Apr 15;5(8):100762. doi: 10.1016/j.jhepr.2023.100762. eCollection 2023 Aug.
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a severe malignant tumour that shows only modest responses to immunotherapy. We aimed to identify the spatial immunophenotypes of iCCA and delineate potential immune escape mechanisms.
Multiplex immunohistochemistry (mIHC) was performed to quantitatively evaluate the distribution of 16 immune cell subsets in intratumour, invasive margin and peritumour areas in a cohort of 192 treatment-naïve patients with iCCA. Multiregion unsupervised clustering was used to determine three spatial immunophenotypes, and multiomics analyses were carried out to explore functional differences.: iCCA displayed a region-specific distribution of immune cell subsets with abundant CD15 neutrophil infiltration in intratumour areas. Three spatial immunophenotypes encompassing inflamed (35%), excluded (35%) and ignored (30%) phenotypes were identified. The inflamed phenotype showed characteristics of abundant immune cell infiltration in intratumour areas, increased PD-L1 expression and relatively favourable overall survival. The excluded phenotype with a moderate prognosis was characterized by immune cell infiltration restricted to the invasive margin or peritumour areas and upregulation of activated hepatic stellate cells, extracellular matrix and Notch signalling pathways. The ignored phenotype, with scarce immune cell infiltration across all subregions, was associated with MAPK signalling pathway elevation and a poor prognosis. The excluded and ignored phenotypes, constituting non-inflamed phenotypes, shared features of an increased angiogenesis score, TGF-β and Wnt-β catenin pathway upregulation and were enriched for mutations and fusions.
We identified three spatial immunophenotypes with different overall prognoses in iCCA. Tailored therapies based on the distinct immune evasion mechanisms of the spatial immunophenotypes are needed.
The contribution of immune cell infiltration in the invasive margin and peritumour areas has been proved. We explored the multiregional immune contexture of 192 patients to identify three spatial immunophenotypes in intrahepatic cholangiocarcinoma (iCCA). By integrating genomic and transcriptomic data, phenotype-specific biological behaviours and potential immune escape mechanisms were analysed. Our findings provide a rationale to develop personalized therapies for iCCA.
肝内胆管癌（iCCA）是一种严重的恶性肿瘤，对免疫疗法的反应有限。我们旨在确定iCCA的空间免疫表型，并描述潜在的免疫逃逸机制。
对192例未经治疗的iCCA患者队列进行多重免疫组化（mIHC），以定量评估肿瘤内、浸润边缘和瘤周区域16种免疫细胞亚群的分布。采用多区域无监督聚类确定三种空间免疫表型，并进行多组学分析以探索功能差异。iCCA显示免疫细胞亚群的区域特异性分布，肿瘤内区域有丰富的CD15中性粒细胞浸润。确定了三种空间免疫表型，包括炎症型（35%）、排除型（35%）和忽略型（30%）。炎症型在肿瘤内区域表现为丰富的免疫细胞浸润、PD-L1表达增加和相对较好的总生存期。排除型预后中等，其特征是免疫细胞浸润局限于浸润边缘或瘤周区域，以及活化肝星状细胞、细胞外基质和Notch信号通路的上调。忽略型在所有亚区域免疫细胞浸润稀少，与MAPK信号通路升高和预后不良相关。排除型和忽略型构成非炎症型，具有血管生成评分增加、TGF-β和Wnt-β连环蛋白通路上调的共同特征，并且富集了 突变和 融合。
我们在iCCA中确定了三种总体预后不同的空间免疫表型。需要基于空间免疫表型独特的免疫逃逸机制进行针对性治疗。
已证实免疫细胞浸润在浸润边缘和瘤周区域的作用。我们研究了192例患者的多区域免疫背景，以确定肝内胆管癌（iCCA）的三种空间免疫表型。通过整合基因组和转录组数据，分析了表型特异性的生物学行为和潜在的免疫逃逸机制。我们的研究结果为开发iCCA的个性化治疗提供了理论依据。
