文章：

患者来源的滤泡性淋巴瘤球状体重现淋巴结信号传导和免疫特征，揭示半乳糖凝集素-9为新型免疫治疗靶点

Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target

原文发布日期：2024-05-02

DOI: 10.1038/s41408-024-01041-7

类型: Article

开放获取: 是

英文摘要：

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.
 

摘要翻译： 

滤泡性淋巴瘤（FL）作为最常见的惰性非霍奇金淋巴瘤，是免疫肿瘤微环境（TME）参与疾病发生、进展及异质性临床结局的典型范例。本研究首次构建了FL患者来源淋巴瘤类球体（FL-PDLS），该模型涵盖了FL淋巴结（LNs）中关键的免疫细胞及TME特征。FL-PDLS形成盘状三维结构，由增殖的B细胞、T细胞以及具有中间M1/M2表型的巨噬细胞组成。该模型重现了FL-LN中最相关的B细胞转录通路（包括增殖、表观遗传调控、mTOR、适应性免疫系统等）。FL-PDLS中的T细胞区室保留了CD4亚群（滤泡辅助性T细胞、调节性T细胞及滤泡调节性T细胞），并涵盖了CD4与CD8群体中的活化/耗竭表型谱系。此外，该系统适用于化学疗法和免疫疗法测试，能够复现临床观察结果。通过FL-PDLS研究发现，可溶性半乳糖凝集素-9会限制利妥昔单抗、利妥昔单抗联合纳武利尤单抗/TIM-3的抗肿瘤活性。阻断半乳糖凝集素-9可增强利妥昔单抗疗效，这提示半乳糖凝集素-9可作为FL的新型免疫治疗靶点。综上，FL-PDLS保持了恶性B细胞与免疫性淋巴结微环境之间的交互作用，构成了在患者来源系统中进行药物筛选的稳健多元化临床前工具，推动了个体化治疗策略的发展。

原文链接：

Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target