Abstract: SA-PO1228
Integrated Spatial and Single-Cell Transcriptomics of Human Kidney Biopsies Reveals Distinct Immune Architecture in Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis
Session Information
- Onconephrology: Epidemiological Trends, Risk Stratification, and Clinical Outcomes
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Arai, Hiroyuki, Washington University in St Louis, St. Louis, Missouri, United States
- Qin, Qian, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Gao, Ce, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Tran, Miles, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Shah, Sujal I., Brigham and Women's Hospital, Boston, Massachusetts, United States
- Wei, Kevin, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Murakami, Naoka, Washington University in St Louis, St. Louis, Missouri, United States
Background
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their clinical benefit is hampered by immune-related adverse events (irAEs). Clinical characteristics of renal irAE, particularly ICI-associated acute interstitial nephritis (ICI-AIN), are well reported, but its underlying mechanisms remain poorly understood.
Methods
To elucidate the multicellular interactions driving ICI-AIN, we integrated CosMx high-plex spatial transcriptomics (319,141 cells) with single-cell formalin-fixed, paraffin embedded (FFPE) RNA sequencing (10X Genomics Flex (Fixed RNA) Assay; scFFPE) (61,391 cells) of paired FFPE kidney biopsy specimens from four cases; two ICI-AIN, one drug-induced AIN, one acute T cell-mediated rejection (TCMR). scFFPE-derived transcriptional signatures were projected onto CosMx data to integrate transcriptome-wide profiling with spatially resolved tissue analysis. We investigated ICI-AIN-specific transcriptomic alterations by analyzing integrated datasets of CosMx and scFFPE.
Results
scFFPE profiling revealed ICI-AIN-specific transcriptional programs across tubular, immune, and myeloid lineages, including co-inhibitory receptor signature, myeloid activation signature, and tubular injury-associated programs. Projection of these signatures on CosMx data demonstrated distinct differentially expressed gene signatures in ICI-AIN compared to drug-induced AIN and TCMR, consistently across both platforms. Spatial analysis uncovered a distinct immune architecture in ICI-AIN, including increased immune enrichment near tubular epithelial cells and enhanced proximity between co-inhibitory-high T cells and activated myeloid cells. Expression of CXCR3 and its ligands CXCL9 and CXCL10 was enriched in ICI-AIN, suggesting their potential roles in its pathogenesis.
Conclusion
Our study demonstrates that ICI-AIN exhibits a spatially organized immune architecture within peritubular regions, through integration of paired scFFPE transcriptomics and CosMx spatial profiling of kidney biopsies. CXCL9/10–CXCR3 axis may play an important role in the pathogenesis of ICI-AIN. This multimodal framework provides a foundation for analyzing human kidney biopsy specimens by leveraging the complementary strengths of spatial transcriptomics and scFFPE.
Funding
- NIDDK Support