Cirauqui Cristina, Ojeda Laura, Otano Itziar, Pazos Irene, Santos Alba, Garrido-Martín Eva M, Yagüe Patricia, Ramos-Paradas Javier, Molina-Pinelo Sonia, Roncador Giovanna, Solórzano José Luis, Muñoz M Teresa, Cozar Patricia, Plaza Patricia, Suárez Rocío, Jiménez Marta, Moreno Roberto, Rosado Arantxa, Gámez Pablo, García-Luján Ricardo, Zugazagoitia Jon, Sweet-Cordero E Alejandro, Barbacid Mariano, Carnero Amancio, Ferrer Irene, Paz-Ares Luis
H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute Hospital 12 de Octubre (imas12)/Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Spanish Center for Biomedical Research Network in Oncology (CIBERONC), Madrid, Spain.
Clin Transl Med. 2025 Jul;15(7):e70374. doi: 10.1002/ctm2.70374.
Interleukin-11 (IL-11) has emerged as a significant player in tumourigenesis, with implications across various cancer types. However, its specific role in driving tumour progression in lung adenocarcinoma (LUAD) remains elusive. IL-11's multifaceted impact on both tumour cells and the tumour microenvironment underscores its potential as a therapeutic target in LUAD. This study aims to unravel the involvement of IL-11 in LUAD progression and its influence on the tumour microenvironment.
Here, we used transcriptomic and digital spatial profiling analyses together with clinic data from two retrospective LUAD patient cohorts. LUAD cell lines genetically engineered to overexpress or to silence IL-11 or its receptor (IL-11RA) were used for in vitro functional analysis and for in vivo experiments. Additionally, we used three different in vivo models: patient-derived xenografts (PDXs), tobacco-exposed mice and genetically engineered mouse models. A neutralising monoclonal antibody against IL-11RA was produced and tested.
Our findings revealed a pivotal role for IL-11 in driving tumourigenesis across various mouse models, highlighting its capacity to modulate tumour immunity towards an immunosuppressive microenvironment. Moreover, we observed a correlation between IL-11 expression and poorer patient outcomes in LUAD. Notably, therapeutic targeting of IL-11RA with a neutralising antibody demonstrated significant anti-tumour efficacy in a PDX model.
The IL-11/IL-11RA axis emerges as a critical driver of LUAD tumourigenesis, exerting its effects through enhanced tumour cell proliferation and remodelling of the tumour microenvironment. Our study highlights the therapeutic potential of disrupting this axis, suggesting that patients exhibiting elevated IL-11 levels may benefit from therapies targeting the IL-11/IL-11RA pathway.
白细胞介素-11（IL-11）已成为肿瘤发生过程中的一个重要因素，对多种癌症类型均有影响。然而，其在肺腺癌（LUAD）肿瘤进展中的确切作用仍不清楚。IL-11对肿瘤细胞和肿瘤微环境具有多方面的影响，这凸显了其作为LUAD治疗靶点的潜力。本研究旨在揭示IL-11在LUAD进展中的作用及其对肿瘤微环境的影响。
在此，我们结合两个LUAD患者回顾性队列的临床数据，使用转录组学和数字空间分析。对经基因工程改造以过表达或沉默IL-11或其受体（IL-11RA）的LUAD细胞系进行体外功能分析和体内实验。此外，我们使用了三种不同的体内模型：患者来源的异种移植模型（PDX）、烟草暴露小鼠和基因工程小鼠模型。制备并测试了一种针对IL-11RA的中和单克隆抗体。
我们的研究结果揭示了IL-11在多种小鼠模型肿瘤发生中的关键作用，突出了其调节肿瘤免疫以形成免疫抑制微环境的能力。此外，我们观察到LUAD中IL-11表达与患者较差的预后之间存在相关性。值得注意的是，在PDX模型中，用中和抗体对IL-11RA进行治疗性靶向显示出显著的抗肿瘤疗效。
IL-11/IL-11RA轴是LUAD肿瘤发生的关键驱动因素，通过增强肿瘤细胞增殖和重塑肿瘤微环境发挥作用。我们的研究突出了破坏该轴的治疗潜力，表明IL-11水平升高的患者可能从针对IL-11/IL-11RA途径的治疗中获益。
