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Immune Checkpoint Biomarkers Galectin-9 and TIM-3 Predict Cancer Mortality in Obstructive Sleep Apnoea
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Elena Díaz-García1,2,16, Enrique Alfaro1,2,3,16, Paula Pérez-Moreno1,2,16, Cristina López Fernández1,2,16, Aldara García-Sánchez1,4,16, Miguel Ángel Martínez-García5,16, Eva Mañas4,16, Irene Cano-Pumarega3,16, Raquel Casitas1,2,16, Francisco Campos-Rodríguez1,6,16, Manuel Sánchez-de-la-Torre1,7,16, Eduardo Nagore8,16, Antonio Martorell-Calatayud9,16, Luis Hernández Blasco10,11,16, Esther Pastor12,16, Jorge Abad-Capa1,13,16, Josep María Montserrat1,14,16, Valentín Cabriada-Nuño15,16, Jaime Corral-Peñafiel1,17,16, Eva Arias18,16..., Olga Mediano1,19,16, María Somoza-González20,16, Joan Dalmau-Arias21,16, Isaac Almendros1,22,23,16, Fernanda Troncoso-Acevedo1,24,16, Carolina Gotera-Rivera24,16, Teresa Pérez-Warnisher25,16, Germán Peces-Barba1,24,16, Luis M. Seijo1,25,16, David Gozal26,16, Francisco García-Rio1,2,3,16,#,
Corresponding author
fgr01m@gmail.com

Correspondence: Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046-Madrid, Spain
,
Carolina Cubillos-Zapata1,2,16,#Ver más
1 Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Madrid, Spain
2 Respiratory Diseases Group, Respiratory Diseases Department, Hospital La Paz Institute for Health Research – IdiPAZ, Madrid, Spain
3 Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
4 Servicio de Neumología, Hospital Universitario Ramón y Cajal, Madrid, Spain
5 Respiratory Department, Hospital Universitario y Politecnico la Fe, Valencia, Spain
6 Respiratory Department, Hospital Universitario de Valme, IBIS, Seville, Spain
7 Group of Precision Medicine in ChronicDiseases, Hospital Universitari Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
8 Dermatology Department, Instituto Valenciano de Oncologia, Valencia, Spain
9 Dermatology Department, Hospital de Manises, Valencia, Spain
10 Respiratory Department, ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
11 Departamento Medicina Clinica, Universidad Miguel Hernandez, Elche, Spain
12 Respiratory Department, Hospital san Juan de Alicante, Alicante, Spain
13 Respiratory Department, Centro de investigacionBiomedica, Hospital GermansTrias i Pujol, Madrid, Spain
14 Respiratory Department, Hospital Clinic- IDIBAPS, Barcelona, Spain
15 Respiratory Department, Hospital Universitario Cruces, Bilbao, Spain
16 Respiratory Department, Hospital Universitario Ramon y Cajal, Madrid, Spain
17 Respiratory Department, Hospital Universitario S. Pedro Alcantara, Caceres, Spain
18 Respiratory Department, Hospital 12 de Octubre, Madrid, Spain
19 Respiratory Department, Hospital Universitario de Guadalajara, Guadalajara, Spain
20 Pneumology Department, Hospital Consorcio Terrassa, Barcelona, Spain
21 Dermatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
22 Unitat de Biofisica i Bioenginyeria, Facultat de Medicina i Ciencies de la Salut, Universitat de Barcelona, Barcelona, Spain
23 Institut d’InvestigacionsBiomediques August Pi iSunyer (IDIBAPS), Barcelona, Spain
24 Servicio de Neumología, IIS-Fundación Jiménez Díaz, Madrid, Spain
25 Clínica Universidad de Navarra, Madrid, Spain
26 Office of the Dean, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
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Article information
Abstract

Objectives: Obstructive sleep apnoea (OSA) has been associated with increased cancer risk and mortality, yet specific biomarkers for patient stratification remain lacking. This study explores the role of immune checkpoint biomarkers, soluble Galectin-9 (sGalectin-9) and TIM-3 (sTIM-3), in identifying OSA patients at higher risk of cancer-related mortality.

Methods: We conducted a multicohort, prospective observational study including 684 patients, with and without cancer, who underwent sleep studies. Plasma levels of sGalectin-9 and sTIM-3 were assessed using bead-based multiplexed assays. In vitro and ex vivo models were employed to investigate the pathogenic mechanisms underlying biomarker upregulation and their immunological impact.

Results: In severe OSA patients with melanoma or lung cancer, sGalectin-9 and sTIM-3 were associated with tumour aggressiveness and with an increased mortality risk. In the three study cohorts, biomarker levels were higher in severe OSA patients than in the other groups. In non-cancer OSA patients’ monocyte intracellular Galectin-9 and T-lymphocyte membrane-bound TIM-3 were upregulated. Experimental data revealed that intermittent hypoxia drove the expression of these biomarkers, which were positively associated with inflammatory mediators and inversely related to T-cell proliferation and infiltration. These findings underscore a mechanistic link between hypoxemia and immune suppression.

Interpretation: sGalectin-9 and sTIM-3 are promising prognostic biomarkers for medium- to long-term survival in OSA patients with melanoma or lung cancer. Their upregulation highlights a potential pathophysiological pathway connecting OSA-induced hypoxemia to cancer aggressiveness through immune modulation. Further validation could inform risk stratification and personalised therapeutic strategies.

Keywords:
Immune checkpoints
sCD25
sleep apnoea
melanoma
lung cancer
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Francisco García-Río and Carolina Cubillos-Zapata share co-last authorship.

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