Kidney international reports · 2026
Spatial Transcriptomics and Mechanisms of Immune Checkpoint Inhibitor-Associated Interstitial Nephritis.
СтатьяНазвание и аннотация: Перевод в очереди
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Qin Qian, Ostendorf Lennard, Wells Sophia L, Gao Ce, Tran Miles, Alikhan Firasat M, Zhang Xiwen, Chewcharat Api, Rider Robert S, Prell Sean A, Chowdhury Raad B, Weins Astrid, Shah Sujal I, Mistry Kavita, Bowman Teresa, Villani Alexandra-Chloe, LeBoeuf Nicole R, Selamet Umut, Ravi Katherine Scovner, Sharon Elad, Leaf David E, Moledina Dennis G, Sise Meghan E, De Vlaminck Iwijn, Rao Deepak A, Wei Kevin, Gupta Shruti
Аннотация
INTRODUCTION: Immune 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 such as CXCL9, 10, and 11; however, the mechanisms of inflammation in ICI-AIN are not well-understood.
METHODS: We applied a subcellular 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).
RESULTS: Across 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-γ) and/or signal transducer and activator of transcription 1 (STAT1) signaling as strongly increased in ICI-AIN compared with ICI-ATN. Although 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-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches.
CONCLUSION: Spatial transcriptomics thus revealed novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN, with IFN-γ-producing CD8+ T cells as potential drivers of ICI-AIN.
METHODS: We applied a subcellular 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).
RESULTS: Across 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-γ) and/or signal transducer and activator of transcription 1 (STAT1) signaling as strongly increased in ICI-AIN compared with ICI-ATN. Although 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-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches.
CONCLUSION: Spatial transcriptomics thus revealed novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN, with IFN-γ-producing CD8+ T cells as potential drivers of ICI-AIN.