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Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint
Samy Hakroush1, Sarah Birgit Kopp2, Désirée Tampe2
1Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
Context:
Due to recent advantages in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death protein 1-ligand 1 (PD-L1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) in the kidney observed in patients receiving ICIs and the most common biopsy-proven diagnosis in patients who develop acute kidney injury (AKI). Based on previous reports, AIN in patients receiving ICIs is associated with tubular positivity for PD-L1, implicating that PD-L1 positivity reflects susceptibility to develop renal complications with these agents. It remains unclear if PD-L1 positivity is acquired specifically during ICI therapy or expressed independently in the kidney.
Methods:
PD-L1 was analyzed in experimental mouse models of ischemia-reperfusion injury (IRI), folic acid-induced nephropathy (FAN), unilateral ureteral obstruction (UUO), and nephrotoxic serum nephritis (NTN) by immunostaining, SDS-PAGE, and subsequent immunoblotting. In addition, we included a total number of 87 human kidney samples (six renal biopsies with AIN related to ICI therapy, 13 nephrectomy control kidneys, and 68 ICI-naïve renal biopsies with various underlying kidney diseases to describe PD-L1 expression.
Results:
We here report distinct PD-L1 expression in renal compartments in multiple murine models of kidney injury and human cases with various underlying kidney diseases, including ICI-related AIN and renal pathologies independent of ICI therapy. PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. In addition, we provide evidence that tubular PD-L1 positivity in the kidney is associated with detection of urinary PD-L1+ tubular epithelial cells.
Conclusion:
Our study implicates that PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. Because non-invasive detection of PD-L1+ cells in corresponding urine samples correlates with intrarenal PD-L1 positivity, it is attractive to speculate that further non-invasive detection of PD-L1+ cells may identify patients at risk for ICI-related AIN.
Insights
Programmed cell death protein 1-ligand 1 (PD-L1) is often present in kidney diseases unrelated to immune checkpoint inhibitors (ICIs). PD-L1 positivity may indicate a risk for acute kidney injury and acute interstitial nephritis in patients receiving ICIs.
Area of Science:
- Nephrology
- Oncology
- Immunology
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 are vital cancer therapies.
- Acute interstitial nephritis (AIN) is a significant kidney complication of ICIs.
- PD-L1 positivity in kidney tubules is linked to ICI-related AIN, but its origin is unclear.
Purpose of the Study:
- To investigate PD-L1 expression in the kidney across various injury models and human kidney diseases.
- To determine if PD-L1 positivity is acquired during ICI therapy or pre-exists.
- To explore the potential of PD-L1 as a biomarker for ICI-induced kidney injury.
Main Methods:
- Analyzed PD-L1 expression in murine kidney injury models (IRI, FAN, UUO, NTN) using immunostaining and immunoblotting.
- Examined 87 human kidney samples: 6 ICI-related AIN, 13 control, and 68 ICI-naïve biopsies.
- Correlated intrarenal PD-L1 positivity with urinary PD-L1+ tubular epithelial cells.
Main Results:
- Distinct PD-L1 expression patterns were observed in murine kidney injury models.
- PD-L1 is frequently expressed in human renal pathologies independent of ICI therapy.
- Tubular PD-L1 positivity correlated with the presence of urinary PD-L1+ cells.
Conclusions:
- PD-L1 expression in the kidney is common in various pathologies, irrespective of ICI treatment.
- Pre-existing PD-L1 positivity may predispose individuals to acute kidney injury and AIN from ICIs.
- Urinary detection of PD-L1+ cells offers a potential non-invasive method to identify patients at risk for ICI-related AIN.
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