WS10.04Programmed cell death 1 receptor axis blockade enhances antigen-specific T cell proliferation in paediatric cystic fibrosis

Abstract

Objectives

Cystic Fibrosis (CF) is associated with recurrent pulmonary infections and high morbidity. Chronic infections can produce CD4+ T lymphocyte (CD4 T cell) exhaustion, characterized by overexpression of the Programmed Cell Death 1 Receptor (PD-1). Rare studies have assessed the role of the PD-1/PD-L1 (ligand) pathway in CF-associated immune dysregulation. We investigated CD4 T cell exhaustion in a cohort of pediatric CF patients and evaluated CD4 T cell rescue after blockade of the PD-1/PD-L1 axis.

Methods

Cross-sectional monocentric study including pediatric CF patients and controls. PD-1 expression was measured on total and memory CD4 T cells by mass cytometry. Antigen-specific CD4 T cell proliferation capacity in response to CF-relevant antigens stimulation (Staphylococcus aureus (Sa), or Pseudomonas aeruginosa (Pa)), was assessed using a CFSE-based flow cytometry assay in absence/presence of anti-PD-L1 blockade antibody.

Results

We included 25 pediatric CF patients and 7 controls (56% and 86% females, median age 11 and 9 years, respectively). No significant differences were observed between the two groups in terms of 1) PD-1 expression on total and memory CD4 T cells and 2) antigen-specific CD4 T cell proliferation capacity. However, PD-1/PD-L1 blockade significantly increased bacteria-specific CD4 T cell proliferation only in CF patients for Pa (n=20, p<0.001) and Sa (n=12, p=0.02). No correlation was found between PD-1 expression on CD4 T cells, nor with antigen-specific T cell proliferative capacity, with markers of disease severity (clinico-microbiological or radiological parameters) in CF patients.

Conclusion

To our knowledge, this is the first study in pediatric CF patients showing enhanced Sa- and Pa-specific CD4 T cell proliferation after PD-1/PD-L1 blockade, despite stable PD-1 levels. Further understanding of the precise mechanism is needed, as PD-1/PD-L1 immunotherapy may represent a future therapeutic option for selected CF patients.