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

Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common histopathological finding among patients with ICI-associated acute kidney injury (ICI-AKI). However, mechanisms of inflammation in ICI-AIN are not well-understood. Using sub-cellular spatial transcriptomics (Xenium Prime 5K), we compared the cellular composition of kidney biopsy tissue from 8 patients (4 with ICI-AIN, 4 ICI-treated patients with acute tubular necrosis [ICI-ATN]). Through spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-γ)/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-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signalling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. Spatial transcriptomics thus reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN, with IFN-γ-producing CD8+ T cells as likely key drivers of ICI-AIN and therefore potential future therapeutic targets.免疫检查点抑制剂相关急性间质性肾炎（immune checkpoint inhibitor-associated acute interstitial nephritis, ICI-AIN）是免疫检查点抑制剂相关急性肾损伤（immune checkpoint inhibitor-associated acute kidney injury, ICI-AKI）患者中最常见的病理组织学表现。然而，目前学界对ICI-AIN的炎症发生机制尚未完全阐明。本研究采用亚细胞空间转录组学（Xenium Prime 5K）技术，对8例患者的肾脏活检组织的细胞构成进行了对比分析：其中4例为ICI-AIN患者，剩余4例为接受免疫检查点抑制剂治疗后合并急性肾小管坏死（acute tubular necrosis, ICI-ATN）的患者。通过空间感知的细胞邻域分类方法，研究团队鉴定出了对应肾单位各部分的细胞生态位，同时还识别出纤维化与炎症生态位。基因通路分析结果显示，相较于ICI-ATN组，ICI-AIN组中干扰素-γ（interferon-gamma, IFN-γ）/STAT1信号通路的激活水平显著升高。尽管ICI-AIN组内所有炎症生态位均呈现富集，但CD8+ T细胞浸润与促炎髓系细胞构成了主要的免疫生态位。空间生态位互作分析揭示，CD8+ T细胞来源的IFN-γ可能诱导髓系细胞产生促炎程序，促使其分泌CXCL9、CXCL10与CXCL11。此外，ICI-AIN组中的IFN-γ信号通路激活与肾小管生态位的氧化磷酸化水平降低存在相关性。综上，空间转录组学技术为解析ICI-AIN与ICI-ATN的病理生理学差异提供了全新视角，产IFN-γ的CD8+ T细胞可能是ICI-AIN的关键驱动因素，亦有望成为未来的潜在治疗靶点。