Single-cell RNA sequencing reveals conserved T cell populations across kidney tissue and urine of patients with immune checkpoint inhibitor nephritis 2262974

Abstract

Abstract Introduction Immune checkpoint inhibitors inhibit the negative regulation of T cells, leading to both anti-tumor activity and immune-related adverse events such as acute interstitial nephritis (ICI-AIN). The immunologic drivers of ICI-AIN are unknown. We hypothesized that both resident and circulating CD8+ T cell subsets are present in ICI-AIN and that they are conserved across kidney tissue and the urine sediment. Methods To characterize the cellular populations that are enriched in ICI-AIN, we used scRNAseq to analyze epithelial and immune cells in kidney tissue and urine from a cohort of 25 patients with biopsy-proven or clinically-adjudicated ICI-AIN, 12 ICI-treated controls with non-AIN AKI, 12 ICI-treated controls with stable kidney function, and 12 ICI-naive patients with stable kidney function prior to ICI initiation. A total of ∼250,000 cells were analyzed and revealed 24 transcriptionally distinct cell subsets, including CD8+ and CD4+ T cells, NK cells, B cells, myeloid cells, renal tubular epithelial cells, and urogenital epithelial cells. Results A range of T cell subsets was identified, existing on a phenotypic spectrum spanning circulation (KLF2) to residency (ITGAE), and cytotoxicity (IFNG, GZMK) to exhaustion (TIGIT). These cell subsets were conserved across both kidney tissue and urine. Gene expression analysis in ICI-AIN samples revealed populations of CD8+ T cells expressing CXCR3 and myeloid cells expressing the interferon-y-stimulated ligands CXCL9/10, suggesting potential cell-cell interactions. Conclusion Taken together, our data contribute to improved understanding of the cellular perturbations in ICI-AIN and reinforce a role for the IFN-y pathway in driving ICI-AIN. The conservation of T cell types observed across kidney tissue and urine suggests the potential for development of a non-invasive urine-based diagnostic test for ICI-AIN. Funding Source American Kidney Fund Clinical Scientist in Nephrology Award; NIH/NIDDK Topic Categories Immune Mechanisms of Human Disease (HUM)