肝内胆管癌免疫微环境中的临床预后剂和靶标
Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma
影响因子:6.30000
分区:医学2区 / 免疫学2区 肿瘤学2区
发表日期:2024
作者:
Isis Lozzi, Alexander Arnold, Matthias Barone, Juliette Claire Johnson, Bruno V Sinn, Johannes Eschrich, Pimrapat Gebert, Ruonan Wang, Mengwen Hu, Linda Feldbrügge, Anja Schirmeier, Anja Reutzel-Selke, Thomas Malinka, Felix Krenzien, Wenzel Schöning, Dominik P Modest, Johann Pratschke, Igor M Sauer, Matthäus Felsenstein
摘要
肝内胆管癌（ICC）是一种预后不良且治疗方案有限的疾病。我们研究了肿瘤免疫微环境（时间），以鉴定疾病预后的预测因素并探索治疗性调节的靶标。在2008 - 2019年期间，诊断为接受ICC的患者（n = 139）在未经新辅助治疗疗法的情况下接受治疗性手术的患者（n = 139）收集了Liver组织样品。对发现队列的样品（n = 86）在组织微阵列（TMA）上进行了免疫组织化学分析，以表达CD68，CD3，CD4，CD8，FOX8，FOXP3，PD-L1，STAT1，STAT1和P-STAT1在肿瘤核心和基质区域。使用QUPATH软件对结果进行数字分析，并与临床病理学特征相关。为了验证与时间相关的生物标志物，我们在验证队列中进行了多重成像质量细胞仪（IMC）（n = 53）.cd68+细胞是ICC时期的主要免疫细胞类型。 CD4+高T细胞密度与更好的总生存率（OS）相关。预测模型与验证队列共同证实了CD4+细胞的相关性，在基质中免疫细胞的PD-L1表达和N阶段在整体疾病结果上的相关性。反过来，IMC分析表明，无声的CD3+ CD4+簇成反比生存。在注释的免疫细胞簇中，PD-L1最相关地用CD4+ FOXP3+细胞表达。具有高密度免疫细胞（“热”簇）的肿瘤子集与PD-L1表达相关，并且可以鉴定一组免疫检查点抑制（ICI）的候选者。最终，较高水平的STAT1表达与较高的淋巴细胞浸润和PD-L1表达有关。这些结果突出了CD4+ T细胞在免疫反应中针对ICC的重要性。其次，具有“热”时间的肿瘤子集代表了ICI的潜在候选者，而STAT1途径的刺激可能是将“冷”变成ICC中“热”时间的潜在目标。
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation.Liver tissue samples were collected during 2008-2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53).CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC.