Abstract
BACKGROUND: Invasive mould infections (IMI) cause substantial morbidity and mortality in populations at risk. Novel treatment approaches are urgently needed. Targeting immune checkpoints may reverse hyporesponsiveness of the innate and adaptive immune systems. METHODS: In this prospective, observational study, we investigated immune checkpoint expression levels on immune cells in patients with invasive aspergillosis (IA; n = 25) and mucormycosis (MU; n = 7). Healthy controls (HC; n = 5) and patients with matched haematological diseases but without IMI served as control populations (CP; n = 10). Multicolour flow cytometry analysis was used to compare immune cell subsets and the expression of immune-regulatory molecules in peripheral blood mononuclear cells (PBMCs). RESULTS: Lymphocyte subsets and immune phenotypes in PBMCs were similar between patients with IMI and haematological CP, except for regulatory T cells, which were increased in PBMCs of patients with IA and MU compared to HCs. In IA and MU, PBMCs showed increased expression of immune checkpoint molecules compared to healthy controls and matched haematological CP, with this effect being more pronounced in IA than in MU. We found heterogeneous, disease-, molecule-, and patient-specific expression patterns of immune checkpoint molecules. For example, PD-1 expression was highest in MU PBMCs, followed by IA PBMCs, while HC PBMCs showed lower expression levels. Overall mortality in our patient population was 44.0% (IPA) and 80.0% (MU). CONCLUSIONS: We report an immune phenotype consistent with T-cell exhaustion in IMI, indicating potential contributions from haematological treatment, underlying disease, and infection. However, the primary underlying cause remains unclear and requires further investigation. A marker that was notably higher in IMI patients was PD-1, and treatment approaches specifically targeting this molecule may be promising.