Vascularized immunocompetent patient-derived tumor model to predict treatment response for lung cancer patients

This work describes a patient-derived tumoroid model (PDTs) to support precision medicine in lung oncology. The use of human adipose tissue-derived microvasculature and patient-derived PBMCs permits to achieve a physiologically relevant tumor-microenvironment in this 3D tumor model. This study involved ten patients at various stages of tumor progression. The vascularized, immune-infiltrated PDT model could be obtained within two weeks, matching the requirements of the therapeutic decision-making process. Histological and transcriptomic analyses confirmed that the main features from the original tumor were reproduced. The 3D tumor model could be used to determine the dynamics of response to antiangiogenic therapy and platinum-based chemotherapy. Antiangiogenic therapy showed a significant decrease in vascular endothelial growth factor (VEGF)-A expression, reflecting its therapeutic effect in the model. In an immune-infiltrated PDT model, chemotherapy showed the ability to decrease the levels of lymphocyte activation gene-3 protein (LAG-3), B and T lymphocyte attenuator (BTLA) and inhibitory receptors of T cells functions. Overall design: Patient biopsies of tumors and healthy tissues compared to patient derived organoïds / tumoroïds

本研究构建了一种患者来源类器官瘤模型（patient-derived tumoroids, PDTs），用于支持肺癌领域的精准医疗。本研究利用人脂肪组织来源微血管与患者来源外周血单个核细胞（peripheral blood mononuclear cells, PBMCs），在该3D肿瘤模型中构建了具有生理相关性的肿瘤微环境。本研究纳入10例处于不同肿瘤进展阶段的患者。该带血管化、免疫浸润的PDTs模型可在两周内完成构建，契合临床治疗决策的需求。组织学与转录组学分析证实，该模型可重现原发肿瘤的核心特征。该3D肿瘤模型可用于评估抗血管生成治疗与铂类化疗的应答动态。抗血管生成治疗可显著降低血管内皮生长因子A（VEGF-A）的表达水平，印证其在该模型中的治疗效应。在免疫浸润型PDTs模型中，化疗可下调淋巴细胞活化基因3蛋白（LAG-3）、B与T淋巴细胞衰减因子（BTLA）以及T细胞功能抑制性受体的表达水平。整体实验设计：以患者来源类器官与类器官瘤为对照，对比分析患者的肿瘤及健康组织活检样本。