Abstract
ContextDue 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.MethodsPD-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.ResultsWe 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.ConclusionOur 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.
Highlights
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, synonym CD274, B7 homolog 1) and are used in many cancer therapies [1]
By using ischemiareperfusion injury (IRI) as a model of experimental acute kidney injury (AKI), we found PD-L1 induced in early injury at day 3 and 7, whereas renal recovery at day 10 after ischemia resulted in normalization of PD-L1 expression (Figures 1A, B and Supplementary Figure 1A)
Nephrotoxic serum nephritis (NTN) as an established model for experimental glomerulonephritis was associated with PD-L1 upregulation (Figures 1C, D and Supplementary Figure 1B), revealing that damage to distinct compartments of the kidney results in PD-L1 induction
Summary
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, synonym CD274, B7 homolog 1) and are used in many cancer therapies [1]. To AIN, there is increasing recognition that glomerular disease and renal vasculitis are associated with ICI-related kidney injury with reports describing both, nephrotic and nephritic clinical presentations [5, 6]. These observations reveal distinct roles of PD-L1 among different renal compartments dependending on its presence or absence. In the context of ICI-related AKI, PD-L1 expression in distinct renal compartments has not yet been analyzed in human kidneys far. We here aimed to compare compartment-specific expression of PDL1 among ICI-related AIN and ICI-naïve renal pathologies
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