An immune responsive tumor microenvironment imprints into PBMCs and predicts outcome in advanced pancreatic cancer: lessons from the PREDICT trial

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-07-22 DOI:10.1186/s12943-025-02406-7

Anton Lahusen, Manfred P. Lutz, Rui Fang, Martina Kirchner, Sarah Albus, Klaus Kluck, Meinolf Karthaus, Andreas Schwarzer, Gabriele Siegler, Alexander Kleger, Thomas J. Ettrich, Alexander Becher, Sabine Höfling, Jens T. Siveke, Jan Budczies, Andrea Tannapfel, Albrecht Stenzinger, Phyllis Fung-Yi Cheung, Tim Eiseler, Thomas Seufferlein

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Abstract

Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor, only few patients benefit from treatment, and there are few biomarkers. The PREDICT trial examined whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) in aPDAC patients but found no association. We hypothesized that the tumor immune microenvironment (TiME) could correlate with the outcome in this trial and assessed whether tissue features were reflected in peripheral blood. PREDICT patients received 5-FU/LV plus nanoliposomal irinotecan as second-line treatment. We stratified patients by shortest vs. longest TTF2 and analyzed 20 treatment-naïve tumor tissues samples via transcriptomics and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from 82 patients collected prior to second-line therapy underwent flow cytometry and gene expression profiling. A machine learning pipeline integrated PBMC and clinical data to predict second-line outcome including external validation in 30 patients. Long-TTF2 tumors exhibited an immune-active (“hot”) TiME with cytotoxic CXCR3+CD8+-T-cell infiltration. PBMC analysis showed that these immune features were reflected in peripheral blood after one line of treatment. A novel 7-feature PBMC-based model (“TTF2Pred”) accurately predicted TTF2 and overall survival, outperforming clinical or CA19-9 models and was confirmed in an external validation cohort. Long-TTF2 patients exhibited more circulating CXCR3⁺-T-cells and plasmacytoid dendritic cells. Short-TTF2 patients had more platelet-leukocyte aggregates. An immune-active, treatment-naïve TiME predicts a better second-line outcome, and these characteristics imprinted into PBMCs obtained after one line of chemotherapy. We here first describe a minimally invasive, PBMC-based predictor of second-line outcome as a powerful prognostic tool for triaging patients. ClinicalTrials.gov NCT03468335 (registered March 15, 2018).

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一种免疫应答性肿瘤微环境印记进入pbmc并预测晚期胰腺癌的预后：来自PREDICT试验的经验教训

晚期胰腺导管腺癌（aPDAC）的预后特别差，只有少数患者从治疗中受益，而且生物标志物很少。PREDICT试验检查了一线治疗失败时间（TTF1）是否预测了aPDAC患者的二线治疗失败时间（TTF2），但没有发现关联。我们假设肿瘤免疫微环境（TiME）可能与本试验的结果相关，并评估组织特征是否在外周血中得到反映。PREDICT患者接受5-FU/LV加纳米脂质体伊立替康作为二线治疗。我们通过最短和最长的TTF2对患者进行分层，并通过转录组学和免疫组织化学分析20例treatment-naïve肿瘤组织样本。在二线治疗前收集的82例患者外周血单个核细胞（PBMCs）进行了流式细胞术和基因表达谱分析。一个机器学习管道整合PBMC和临床数据来预测二线结果，包括30例患者的外部验证。Long-TTF2肿瘤具有细胞毒性的CXCR3+CD8+- t细胞浸润，表现出免疫活性（“热”）时间。PBMC分析显示，这些免疫特征在一次治疗后反映在外周血中。一种新颖的基于pbmc的7个特征模型（“TTF2 pred”）准确预测了TTF2和总生存期，优于临床或CA19-9模型，并在外部验证队列中得到证实。Long-TTF2患者表现出更多的循环CXCR3 + - t细胞和浆细胞样树突状细胞。Short-TTF2患者有更多的血小板-白细胞聚集。免疫活性，treatment-naïve TiME预测更好的二线结果，这些特征烙印在一线化疗后获得的pbmc中。在这里，我们首先描述了一种微创的、基于pbmc的二线预后预测器，作为对患者进行分诊的有力预后工具。ClinicalTrials.gov NCT03468335（注册于2018年3月15日）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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