Year: 2025
Type: article
Abstract: RATIONALE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
DOI: 10.1002/ctm2.70374
Authors: Cristina Cirauqui, Laura Ojeda, Itziar Otano, Irene Pazos, Alba Santos, Eva M. Garrido‐Martín, Patricia Yagüe, Javier Ramos‐Paradas, Sonia Molina‐Pinelo, Giovanna Roncador, José Luis Solórzano, M. Teresa Muñoz, Patricia Cozar, Patricia Plaza, Rocío Suárez, Marta Jiménez, Roberto Moreno, Arantxa Rosado, Pablo Gámez, Ricardo García‐Luján, Jon Zugazagoitia, E. Alejandro Sweet‐Cordero, Mariano Barbacid, Amancio Carnero, Irene Ferrer, Luis Paz‐Ares
Institutions: Research Institute Hospital 12 de Octubre, Spanish National Cancer Research Centre, Hospital Universitario 12 De Octubre, Centro de Investigación Biomédica en Red de Cáncer, Universidad Autónoma de Madrid, Yale University, Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, MD Anderson Cancer Center Madrid, University of California, San Francisco, Universidad Complutense de Madrid
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,470
Funders: Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades, Fundación Científica Asociación Española Contra el Cáncer, Centro de Investigación Biomédica en Red de Cáncer, Ministerio de Educación y Formación Profesional, Instituto de Salud Carlos III, European Regional Development Fund, National Cancer Institute
Awards: G1075404386, G1225290298, G1280040366, G1439616544, G1605422331, G4974690386, Personalized multimodal therapies for the treatment of lung cancer, G5814584683, Optimización de la terapia con inhibidores covalentes de KRAS-G12C en el Cáncer de Pulmón No Microcítico (CPNM), G6183001954, Caracterización molecular e inmune del cáncer de pulmón no microcítico (CPNM) como base para la personalización de estrategias de inmunoterapia, G6420926828, Interacción de la interleukina 11 (IL11) con el microambiente tumoral en el adenocarcinoma de pulmón, y estudio de su inhibición como estrategia terapéutica, Using Protein Interaction Networks and Combinatorial Screens to target KRAS driven cancer, Caracterización exhaustiva del perfil inmune del cáncer microcítico de pulmón (SCLC): Identificación de nuevas vulnerabilidades terapeúticas y validación funcional, G8508194677, Interferencia epigenética entre las células inmunes y células tumorales de pulmón: potenciales jugadores de la resistencia a la inmunoterapia, G91959584, G978536151
OpenAlex ID: W4412489347