Immune checkpoint activity regulates polycystic kidney disease progression

Area of Science:

• Nephrology
• Immunology
• Oncology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic kidney disorder with limited therapeutic options.
• Immune cells significantly influence ADPKD progression, with CD8+ T cell loss exacerbating the disease.
• Immune checkpoint inhibitors are effective in cancer by reactivating T cells, suggesting potential in ADPKD.

Purpose of the Study:

• To investigate the role of immune checkpoints, specifically PD-1 and CTLA-4, in ADPKD pathogenesis.
• To evaluate the therapeutic potential of targeting these immune checkpoints in preclinical ADPKD models.

Main Methods:

• Utilized orthologous early-onset and adult-onset ADPKD mouse models (Pkd1 p.R3277C).
• Analyzed kidney immune cell populations using flow cytometry, focusing on T cells, macrophages, and epithelial cells.
• Assessed the impact of genetic PD-L1 deletion and antibody-mediated blockade of PD-1 and CTLA-4 on disease severity.

Main Results:

• Increased expression of PD-1, CTLA-4, PD-L1, and CD80 was observed in immune and kidney cells of ADPKD models and human patients, correlating with disease severity.
• Monotherapy with anti-PD-1 or anti-CTLA-4 antibodies did not affect PKD progression.
• Combination therapy with anti-PD-1 and anti-CTLA-4 antibodies improved outcomes in adult-onset ADPKD models, increasing CD8+ T cell activation and reducing regulatory T cells.

Conclusions:

• Immune checkpoint activation is a significant feature of ADPKD.
• Combined blockade of PD-1 and CTLA-4 represents a promising therapeutic strategy for ADPKD.
• Targeting immune checkpoints could offer a novel treatment avenue for ADPKD patients.