Abstract: FR-PO0157
Single-Cell RNA Sequencing Suggests a Role for the Interferon-Gamma Pathway and Failed Repair Epithelial Cell States in Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis
Session Information
- AKI: Mechanisms - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Mistry, Kavita, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Kernin, Isabela, Massachusetts General Hospital, Boston, Massachusetts, United States
- Smith, Neal Patrick, Massachusetts General Hospital, Boston, Massachusetts, United States
- Best, Roya, Massachusetts General Hospital, Boston, Massachusetts, United States
- Stueber, Christopher T, Massachusetts General Hospital, Boston, Massachusetts, United States
- Tuttle, Elizabeth, Massachusetts General Hospital, Boston, Massachusetts, United States
- Sun, Joie, Massachusetts General Hospital, Boston, Massachusetts, United States
- Ambrose, Courtney, Massachusetts General Hospital, Boston, Massachusetts, United States
- Gupta, Shruti, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Reynolds, Kerry, Massachusetts General Hospital, Boston, Massachusetts, United States
- Villani, Alexandra-Chloe, Massachusetts General Hospital, Boston, Massachusetts, United States
- Sise, Meghan E., Massachusetts General Hospital, Boston, Massachusetts, United States
Background
Immune checkpoint inhibitors have revolutionized cancer care, producing durable anti-tumor responses by inhibiting the negative regulation of T cells. However, their use is limited by immune-related adverse events including acute interstitial nephritis (ICI-AIN), which affects 3-5% of patients and often interrupts cancer treatment. The immunologic drivers of ICI-AIN remain unknown. We leveraged single-cell RNA sequencing (scRNAseq) technologies to systematically uncover cellular populations and biological pathways that are enriched in biospecimens from patients with ICI-AIN.
Methods
We used scRNAseq to analyze epithelial and immune cells in kidney tissue, blood 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 epithelial cell subtypes was identified, including failed repair proximal tubule cells (VCAM1, DCDC2A, SEMA5A). A range of T cell subsets was identified, existing on a phenotypic spectrum spanning circulation (KLF2, SELL) to residency (ITGAE), and cytotoxicity (IFNG, GZMK) to exhaustion (TIGIT). These cell subsets were conserved across compartments. 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 epithelial and immune cell perturbations in ICI-AIN and reinforce a role for the IFN-y pathway in driving ICI-AIN. The conservation of immune cell types observed across kidney tissue and urine, and the expression of IFN-y-stimulated genes suggests the potential for development of a non-invasive urine-based diagnostic test for ICI-AIN.
Funding
- NIDDK Support