Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis.
Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis.
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DOI：
10.1172/jci.insight.165108
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发表时间：
2022-12-01
期刊：
影响因子：
8
通讯作者：
Lin, Jamie S
中科院分区：
文献类型：
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作者：
Singh, Shailbala;Long, James P;Lin, Jamie S
三级淋巴结构(TLS)与免疫检查点抑制剂(ICI)治疗后的抗肿瘤反应有关，但缺乏对免疫相关不良事件(IrAE)，如急性间质性肾炎(AIN)的相应观察。我们假设TLS相关的炎症基因信号存在于AIN中，并对36名因ICI发生急性肾损伤(AKI)的参与者进行了基于纳米串的基因表达和多重12-趋化因子谱分析：AIN(18例)、急性肾小管坏死(9例)或HTN肾硬化症(9例)。ICI-AIN组T细胞和B细胞评分增加，Th1-CD8+T细胞轴伴随干扰素-g和肿瘤坏死因子超家族特征。TLS信号在AIN病例中显著增加，并得到组织病理学鉴定的支持。此外，尿TLS信号积分与ICI-AIN诊断相关，但与配对血浆无关。尿CXCL9与组织中CXCL9的表达(Rho0.75，p<；0.001)和区分AIN与非AIN的能力(AUC 0.781，P值0.003)相关性最好。我们首次报道了在irAEs中存在TLS信号，定义了独特的免疫信号，识别了区分ICI-AIN和常见AKI病因的趋化因子标记物，并证明了尿液趋化因子标记物可以作为ICI-AIN诊断的替代指标。
Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification. Furthermore, urinary TLS signature scores correlated with ICI-AIN diagnosis but not paired plasma. Urinary CXCL9 correlated best to tissue CXCL9 expression (rho 0.75, p < 0.001) and the ability to discriminate AIN vs. non-AIN (AUC 0.781, p-value 0.003). For the first time, we report the presence of TLS signatures in irAEs, define distinctive immune signatures, identify chemokine markers distinguishing ICI-AIN from common AKI etiologies and demonstrate that urine chemokine markers may be used as a surrogate for ICI-AIN diagnoses.