Spatial Transcriptomics Identify T Cell-Driven Mechanisms of Kidney Damage in Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis

Abstract

IntroductionImmune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common finding on histopathology among patients with ICI-associated acute kidney injury (ICI-AKI). Patients with ICI-AIN often have T cell-dominant infiltration of the kidney and high tissue levels of CXCR3 ligands like CXCL9, 10, and 11; however, the mechanisms of inflammation in ICI-AIN are not well-understood. MethodsWe applied a sub-cellular spatial transcriptomics platform (Xenium Prime 5K) to compare the cellular composition of kidney biopsy tissue from patients with ICI-AIN with ICI-treated patients with acute tubular necrosis (ICI-ATN). ResultsAcross 8 kidney biopsy specimens (4 with ICI-AIN, 4 with ICI-ATN), we analyzed 332,000 cells, comprising kidney parenchymal cells and infiltrating immune cells. Using a spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to unique fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-{gamma})/STAT1 signaling as strongly increased in ICI-AIN compared to ICI-ATN. While all inflammatory niches were overrepresented in ICI-AIN, CD8+ T cell infiltration and proinflammatory myeloid cells were the dominant immune niches. Spatial niche crosstalk analysis revealed that CD8+ T cell-derived IFN-{gamma} likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-{gamma} signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. ConclusionsSpatial transcriptomics reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN. IFN-{gamma}-producing CD8+ T cells are likely key drivers of ICI-AIN and should be investigated as future therapeutic targets. Translational StatementSpatial transcriptomics may provide insight into differences in the cellular and spatial composition of immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) and ICI-associated acute tubular necrosis (ICI-ATN). Using the novel Xenium 5K platform, we demonstrate that IFN-{gamma}-producing CD8+ T cells are central to the pathogenesis of ICI-AIN, and that CD8+ T cell-derived IFN-{gamma} likely induces a proinflammatory state in myeloid cells, with increased tissue production of CXCL9, 10, and 11. We then show that a reduction in oxidative phosphorylation and an IFN-{gamma}-driven influx of proinflammatory myeloid cells may further drive kidney damage in ICI-AIN. Many of these pathways represent potential druggable targets, and our findings may therefore inform future therapeutic approaches for ICI-AIN.