A73-18 TIGIT and CD25 Immune Checkpoint Dysregulation Associated With Hypoxemia in Obstructive Sleep Apnea

Rationale

Obstructive sleep apnoea (OSA) is characterized by intermittent hypoxemia and is associated with increased cancer incidence, aggressiveness, and mortality. Growing evidence suggests that hypoxemia-driven immune dysregulation, particularly through immune checkpoint pathways, may compromise immune surveillance and promote tumour progression. However, the mechanisms linking OSA-related hypoxemia, immune checkpoint modulation, and cancer outcomes remain incompletely understood.

Methods

We investigated the impact of OSA-associated hypoxemia on immune checkpoint regulation, focusing on the TIGIT and CD25 pathways. Circulating and membrane-bound CD25 expression was analyzed in OSA patients with and without cancer, as well as in cohorts of patients with melanoma and lung cancer. In addition, we studied TIGIT expression in T cells from patients with and without OSA. We also examined the role of hypoxemia—particularly the involvement of hypoxia-inducible factor-1α (HIF-1α)—using a combination of in vitro models. Finally, we evaluated the effect of one year of standard continuous positive airway pressure (CPAP) therapy on TIGIT expression in OSA patients.

Results

OSA patients exhibited increased expression of inhibitory immune checkpoints on T lymphocytes, including membrane-bound TIGIT and CD25, even in the absence of clinically evident cancer. These alterations correlated with hypoxemia severity and were mediated by HIF-1α-dependent pathways under intermittent hypoxia conditions. In parallel, hypoxemia promoted the shedding of CD25, leading to elevated circulating levels of soluble CD25 (sCD25). Importantly, sCD25 levels were associated with tumour aggressiveness parameters in melanoma and lung cancer and predicted increased mortality risk in OSA patients with lung cancer. Long-term CPAP treatment reduced TIGIT expression, highlighting the reversibility of hypoxemia-driven immune checkpoint dysregulation.

Conclusions

Overall, these findings suggest that hypoxemia associated with obstructive sleep apnea (OSA) plays a central role in immune regulation, promoting a T cell exhaustion phenotype characterized by increased expression of markers such as TIGIT and sCD25. These immune alterations are closely linked to impaired antitumor immune responses and are associated with increased tumor aggressiveness and poorer prognosis in OSA patients with cancer, including melanoma and lung cancer. Importantly, the reduction of hypoxemia through CPAP treatment appears to partially reverse these immune dysfunctions, highlighting the clinical relevance of adequate OSA management. In this context, sCD25 emerges as a promising biomarker for risk stratification and mortality prediction in OSA patients with cancer.

This abstract is funded by: Instituto de Salud Carlos III (ISCIII) and European Union, Ayudas Luis Alvarez 2021 FIBHULP