Long James P, Singh Shailbala, Dong Yanlan, Yee Cassian, Lin Jamie S
Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2025 Jan 25;13(1):e010680. doi: 10.1136/jitc-2024-010680.
Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy is required to differentiate ICI-AIN from other causes of acute kidney injury (AKI). However, this invasive approach can lead to morbidity, delayed glucocorticoid treatment for patients with AIN, and unnecessarily prolonged suspension of ICI therapy in non-AIN patients. Delayed or incorrect diagnosis of ICI-AIN is particularly detrimental, as over 50% of patients are at risk of permanent renal damage. Thus, there is an urgent need for non-invasive biomarkers that can rapidly and accurately distinguish ICI-AIN from other causes of AKI.The urine and plasma proteome contain actively secreted proteins that provide real-time insights into dynamic physiological processes. However, identification of effective biomarkers of disease using established technologies such as proximity ligation assays (PLA) and bead-based immunoassays is challenging due to their limited sensitivity and loss of precision in multiplex analysis.To address this, we employed cutting-edge NUcleic acid Linked Immuno-Sandwich Assay (NULISA) technology to measure protein expression in urine and plasma samples from AKI patients undergoing ICI therapy. NULISA offers 10,000-fold greater precision than PLA, enabling quantification of over 200 inflammatory proteins with unprecedented precision. Our analysis revealed that urine was more sensitive and specific than plasma in distinguishing ICI-AIN from non-AIN cases. Pathway analyses highlighted the involvement of JAK-STAT and tumor necrosis factor (TNF) signaling in ICI-AIN pathogenesis. We identified several novel urine biomarkers, including IL-5, Fas, TNFSF4, CD274, IL-20, TNFSF15, TSLP, TREM1 and CCL1 while confirming previously reported markers such as CXCL9 and TNF-α. Using statistical and machine learning methods, we constructed a novel urine biomarker signature-IL-5+Fas-that achieved an area under the curve of 0.94 for diagnosing ICI-AIN.By leveraging high-sensitivity proteomics, we developed a non-invasive strategy for diagnosing ICI-AIN. This approach will enable earlier intervention to mitigate immunotoxicity, preservation of antitumor efficacy of ICI therapy in non-AIN patients, and safe rechallenge of ICI therapy in patients previously treated for ICI-AIN.
免疫检查点抑制剂（ICI）疗法是许多癌症的基石性治疗方法，但它可诱发严重的免疫毒性，包括急性间质性肾炎（AIN）。目前，需要进行肾活检以区分ICI-AIN与急性肾损伤（AKI）的其他病因。然而，这种侵入性方法可能导致发病、AIN患者糖皮质激素治疗延迟以及非AIN患者ICI治疗不必要地长期中断。ICI-AIN的延迟或错误诊断尤其有害，因为超过50%的患者有永久性肾损伤的风险。因此，迫切需要能够快速、准确地将ICI-AIN与AKI的其他病因区分开来的非侵入性生物标志物。
尿液和血浆蛋白质组包含主动分泌的蛋白质，可提供对动态生理过程的实时洞察。然而，使用诸如邻近连接分析（PLA）和基于珠子的免疫分析等成熟技术来鉴定有效的疾病生物标志物具有挑战性，因为它们的灵敏度有限且在多重分析中会损失精度。
为了解决这个问题，我们采用了前沿的核酸连接免疫夹心分析（NULISA）技术来测量接受ICI治疗的AKI患者尿液和血浆样本中的蛋白质表达。NULISA的精度比PLA高10000倍，能够以前所未有的精度对200多种炎症蛋白进行定量。我们的分析表明，在区分ICI-AIN与非AIN病例方面，尿液比血浆更敏感且更具特异性。通路分析突出了JAK-STAT和肿瘤坏死因子（TNF）信号通路在ICI-AIN发病机制中的作用。我们鉴定了几种新的尿液生物标志物，包括IL-5、Fas、TNFSF4、CD274、IL-20、TNFSF15、TSLP、TREM1和CCL1，同时确认了先前报道的标志物，如CXCL9和TNF-α。使用统计和机器学习方法，我们构建了一种新的尿液生物标志物特征——IL-5+Fas——用于诊断ICI-AIN时曲线下面积达到0.94。
通过利用高灵敏度蛋白质组学，我们开发了一种诊断ICI-AIN的非侵入性策略。这种方法将能够进行早期干预以减轻免疫毒性，在非AIN患者中保留ICI治疗的抗肿瘤疗效，并在先前接受过ICI-AIN治疗的患者中安全地重新使用ICI治疗。
