Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.
Front Immunol. 2021 Jan 21;11:624547. doi: 10.3389/fimmu.2020.624547. eCollection 2020.
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.
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.
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.
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.
由于癌症治疗的最新进展，免疫检查点抑制剂（ICI）是一类新型药物，针对程序性细胞死亡蛋白 1（PD-1）或其配体程序性细胞死亡蛋白 1 配体 1（PD-L1），用于许多癌症治疗。急性间质性肾炎（AIN）是接受 ICI 治疗的患者中观察到的一种潜在且有害的免疫相关不良事件（irAE），也是发生急性肾损伤（AKI）的患者最常见的经活检证实的诊断。基于以往的报告，接受 ICI 治疗的患者的 AIN 与 PD-L1 肾小管阳性相关，这表明 PD-L1 阳性反映了对这些药物发生肾并发症的易感性。目前尚不清楚 PD-L1 阳性是否是在 ICI 治疗期间特异性获得的，还是在肾脏中独立表达的。
通过免疫染色、SDS-PAGE 和随后的免疫印迹分析，分析了缺血再灌注损伤（IRI）、叶酸诱导的肾病（FAN）、单侧输尿管梗阻（UUO）和肾毒性血清肾炎（NTN）实验小鼠模型以及总共 87 个人类肾脏样本（与 ICI 治疗相关的 AIN 相关的 6 例肾活检、13 例肾切除术对照肾脏和 68 例 ICI 初治的各种基础肾脏疾病的肾活检）中的 PD-L1。
我们在此报告了在多种肾脏损伤的小鼠模型和具有各种基础肾脏疾病的人类病例中，包括与 ICI 治疗相关的 AIN 和与 ICI 治疗无关的肾脏病理，肾脏中 PD-L1 在多个肾区的独特表达。PD-L1 在与 ICI 治疗无关的各种肾脏病理中经常表达，并且可能是易发生 AKI 和有害免疫相关 AIN 的先决条件。此外，我们提供的证据表明，肾脏中 PD-L1 的管状阳性与尿 PD-L1 管状上皮细胞的检测相关。
我们的研究表明，PD-L1 在与 ICI 治疗无关的各种肾脏病理中经常表达，并且可能是易发生 AKI 和有害免疫相关 AIN 的先决条件。由于相应尿液样本中 PD-L1 细胞的非侵入性检测与肾内 PD-L1 阳性相关，因此推测进一步的 PD-L1 细胞非侵入性检测可能可以识别出有发生 ICI 相关 AIN 风险的患者。
