Lahusen Anton, Lutz Manfred P, Fang Rui, Kirchner Martina, Albus Sarah, Kluck Klaus, Karthaus Meinolf, Schwarzer Andreas, Siegler Gabriele, Kleger Alexander, Ettrich Thomas J, Becher Alexander, Höfling Sabine, Siveke Jens T, Budczies Jan, Tannapfel Andrea, Stenzinger Albrecht, Cheung Phyllis Fung-Yi, Eiseler Tim, Seufferlein Thomas
Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
Department of Gastroenterology, Caritas Klinikum Saarbrücken St. Theresia, Saarbrücken, Germany.
Mol Cancer. 2025 Jul 22;24(1):202. doi: 10.1186/s12943-025-02406-7.
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 CXCR3CD8-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).
晚期胰腺导管腺癌（aPDAC）的预后特别差，只有少数患者能从治疗中获益，且生物标志物很少。PREDICT试验研究了一线治疗失败时间（TTF1）是否能预测aPDAC患者的二线治疗失败（TTF2），但未发现两者之间存在关联。我们推测肿瘤免疫微环境（TiME）可能与该试验的结果相关，并评估了组织特征是否在外周血中有所体现。
PREDICT试验中的患者接受5-氟尿嘧啶/亚叶酸钙联合纳米脂质体伊立替康作为二线治疗。我们根据TTF2的最短与最长时间对患者进行分层，并通过转录组学和免疫组织化学分析了20份未经治疗的肿瘤组织样本。对82例患者在二线治疗前采集的外周血单个核细胞（PBMC）进行了流式细胞术和基因表达谱分析。一个机器学习流程整合了PBMC和临床数据，以预测二线治疗结果，包括在30例患者中进行外部验证。
长TTF2的肿瘤表现出具有细胞毒性CXCR3⁺CD8⁻T细胞浸润的免疫活性（“热”）TiME。PBMC分析表明，经过一线治疗后，这些免疫特征在外周血中有所体现。一种基于PBMC的新型7特征模型（“TTF2Pred”）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。长TTF2的患者表现出更多循环CXCR3⁺T细胞和浆细胞样树突状细胞。短TTF2的患者有更多血小板-白细胞聚集体。
免疫活性的、未经治疗的TiME预示着更好的二线治疗结果，且这些特征会烙印在一线化疗后获得的PBMC中。我们在此首次描述了一种基于PBMC的微创二线治疗结果预测指标，作为一种强大的预后工具用于对患者进行分类。
ClinicalTrials.gov NCT03468335（2018年3月15日注册）
