PD-1 immunobiology in glomerulonephritis and renal cell carcinoma

Abstract

Background Programmed cell death protein (PD)-1 receptors and ligands on immune cells and kidney parenchymal cells help maintain immunological homeostasis in the kidney. Dysregulated PD-1:PD-L1 binding interactions occur during the pathogenesis of glomerulopathies and renal cell carcinoma (RCC). The regulation of these molecules in the kidney is important to PD-1/PD-L1 immunotherapies that treat RCC and may induce glomerulopathies as an adverse event. Methods The expression and function of PD-1 molecules on immune and kidney parenchymal cells were reviewed in the healthy kidney, PD-1 immunotherapy-induced nephrotoxicity, glomerulopathies and RCC. Results PD-1 and/or its ligands are expressed on kidney macrophages, dendritic cells, lymphocytes, and renal proximal tubule epithelial cells. Vitamin D3, glutathione and AMP-activated protein kinase (AMPK) regulate hypoxic cell signals involved in the expression and function of PD-1 molecules. These pathways are altered in kidney disease and are linked to the production of vascular endothelial growth factor, erythropoietin, adiponectin, interleukin (IL)-18, IL-23, and chemokines that bind CXCR3, CXCR4, and/or CXCR7. These factors are differentially produced in glomerulonephritis and RCC and may be important biomarkers in patients that receive PD-1 therapies and/or develop glomerulonephritis as an adverse event Conclusion By comparing the functions of the PD-1 axis in glomerulopathies and RCC, we identified similar chemokines involved in the recruitment of immune cells and distinct mediators in T cell differentiation. The expression and function of PD-1 and PD-1 ligands in diseased tissue and particularly on double-negative T cells and parenchymal kidney cells needs continued exploration. The possible regulation of the PD-1 axis by vitamin D3, glutathione and/or AMPK cell signals may be important to kidney disease and the PD-1 immunotherapeutic response.

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

“…(50)The PD-1/PD-L1 pathway is also increased in several kidney diseases independent of age, but are typically restricted to immune cells (reviewed in (51)) Kidney interstitial dendritic cells and human primary kidney proximal tubular epithelial cells express PD-L1 and PD-L2, where PD-L1 is integral for CD8 T cell tolerance. (52) Noteworthy is that several glomerulopathies have been recorded as a complication of anti-PD-1 immunotherapy. ( 52) We show for the first time that increased expression of PDCD1 in aging human glomeruli is highly clinically significant, correlating with lower kidney function, higher scarring and increased vascular damage.…”

Balancing the Risk-Benefit Ratio of Immune Checkpoint Inhibitor and Anti-VEGF Combination Therapy in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

“…In RCC, the von Hippel-Lindau (VHL) gene is often silenced or lost, which drives the development of a highly vascularized pathology. Notably, PD-1 and its ligands are reported to be expressed on kidney macrophages, dendritic cells, lymphocytes, and renal proximal tubule epithelial cells ( 12 ). These two factors contribute to the immune-suppressive microenvironment.…”

Deep Learning–Based Classification of Epithelial–Mesenchymal Transition for Predicting Response to Therapy in Clear Cell Renal Cell Carcinoma

“…AMP-activated protein kinase (AMPK) acts as an intracellular energy sensor and was significantly lower in Mes subtype compared to Epi subtype ( P < 0.01; Figure 5B ), which negatively regulates fatty acid synthesis and positively regulates mitochondria production ( 21 ). The metabolic shift identified in the Mes group is reported to contribute to the Warburg metabolic phenotype, further enhanced malignancy, immune protection of cancer cells ( 22 ). Furthermore, the GSEA and AMPK complex genes expression validated some of these results ( Figures 5C, D ).…”