Jansson Hannes, Cornillet Martin, Sun Dan, Filipovic Iva, Sturesson Christian, O'Rourke Colm J, Andersen Jesper B, Björkström Niklas K, Sparrelid Ernesto
Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Front Oncol. 2023 Jun 19;13:1169537. doi: 10.3389/fonc.2023.1169537. eCollection 2023.
Systemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank.
Expression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a high-throughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts.
Three preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordance-index of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells.
In conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells.
全身炎症标志物已被确认为胆管癌（BTC）患者的预后因素。本研究的目的是通过分析来自一个大型前瞻性收集的生物样本库的术前血浆样本，评估特定的免疫预后标志物和免疫反应。
采用高通量多重免疫分析法，对2009年至2017年接受BTC切除术的102例患者（肝门部胆管癌n = 46，肝内胆管癌n = 27，胆囊癌n = 29）的血浆中代表适应性和先天性免疫反应的92种蛋白质的表达进行了研究。通过Cox回归分析与总生存期的关联，并进行内部验证和校准。在外部队列中分析了已鉴定标志物和受体/配体的肿瘤组织体积和单细胞基因表达。
三种术前血浆标志物与生存独立相关：TRAIL、TIE2和CSF1，风险比（95%置信区间）分别为0.30（0.16 - 0.56）、2.78（1.20 - 6.48）和4.02（1.40 - 11.59）。使用这三种血浆标志物的术前预后模型的判别能力用一致性指数0.70评估，而术后病理分期模型的一致性指数为0.66。考虑亚组差异，对每种类型的BTC评估预后因素。TRAIL和CSF1是肝内胆管癌的预后因素。在独立队列中，TRAIL受体在肿瘤组织中的表达更高，且在恶性细胞中可见，TRAIL和CSF1由肿瘤内和肿瘤周围的免疫细胞表达。与肿瘤周围免疫细胞相比，肿瘤内TRAIL活性降低，而CSF1活性增加。肿瘤内巨噬细胞中CSF1活性最高，而肿瘤周围T细胞中TRAIL活性最高。
总之，三种术前免疫血浆标志物对BTC手术后的生存具有预后价值，即使与术后病理相比也具有良好的判别能力。TRAIL和CSF1作为肝内胆管癌的预后因素，在肿瘤内和肿瘤周围免疫细胞之间的表达和活性存在显著差异。
