Mechanisms driving acute and chronic kidney function decline after immune checkpoint inhibitor therapy for cancer

项目总结 免疫检查点抑制剂(ICIS)正在给癌症治疗带来革命性的变化，在 多种癌症类型；然而，通过释放T细胞反应，ICIS可以导致与免疫相关的毒性 基本上是任何器官系统，影响60%-80%的受赠者。保守估计，3%-5%的 患者在ICIS后发展为急性间质性肾炎(AIN)，最近的一项研究发现高达40%的患者 在接受ICIS治疗后存活2年的患者将经历快速估计的肾小球滤过率(EGFR)下降 (&gt；3毫升/分钟/年)。关于ICI所致肾损伤的机制，人们知之甚少，就像以前发表的那样。 实地工作一直是描述性的。基于已发表的研究表明明显高细胞毒性T细胞 ICIS后免疫相关不良事件的活动性，我们假设AIN和慢性肾脏疾病 (CKD)存在于T细胞介导的肾小管间质损伤的谱系中。 肾脏。在目标1中，我们将招募25名经活检证实的ici-ain(ici-ain)患者和25名患者。 ICIS后临床判断的血流动力学AKI和配对肾脏的单细胞RNA测序 活检组织、血液和尿液样本，以揭示ICI诱导的AIN的机制。单细胞 肾组织的转录图谱将为ICI的细胞和分子发病机制提供深入的认识。 AIN以及比较血液和尿液特征的明确基准(目标1B)。到时候我们会的 比较血和尿中细胞转录生物标记物(Aim 1C)和细胞因子生物标记物(Aim 1D) ICIS后经活检证实的ICI-AIN患者的血流动力学AKI，以确定ICI-AIN独有的生物标志物 以及在未来的干预研究中靶向的途径。在目标2中，我们将确定 ICIS与远期肾损伤的关系：前瞻性评估血、尿肾损伤生物标志物 接受ICI治疗的黑色素瘤患者两年与对照组早期黑色素瘤患者进行比较 仅接受手术切除，不接受ICIS(目标2A)。了解促进机制 ICIS后肾功能下降，在目标2B中，我们将使用scRNAseq来研究两者之间的相似性 20%EGFR患者血和尿中的免疫和非免疫细胞转录程序 从AIM 1B到ICI-AIN患者的ICIS后下降。总的来说，拟议的研究将揭示 ICI致肾损伤的机制，具有导致ICI-AIN非侵入性诊断的强大潜力， 并对T细胞解除抑制对肾功能的作用产生了重要的生物学见解。这项提议将 利用马萨诸塞州综合医院严重免疫治疗并发症服务的专业知识 医院(MGH)，这是首个由肿瘤学家和研究免疫学的专家组成的多学科团队。 相关的不良事件，以及MGH癌症中心巨大的生物库基础设施，推动了 这些创新目标的可行性。这个Stephen I.Katz早期调查者研究项目Grant是一个 首席研究员的新方向，启动了一个肿瘤肾脏学的转译研究计划。

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) are revolutionizing cancer care, producing durable anti-tumor responses in multiple cancer types; however, by unleashing T-cell responses, ICIs can lead to immune-related toxicities in essentially any organ system, affecting 60-80% of recipients. It is conservatively estimated that 3-5% of patients develop acute interstitial nephritis (AIN) after ICIs, and a recent study found that up to 40% of patients that survive 2 years after receiving ICIs will experience rapid estimated glomerular filtration rate (eGFR) decline (>3mL/min/year). Very little is known about the mechanisms of ICI-induced kidney injury, as all prior published work in the field has been descriptive. Building on published studies showing distinctly high cytotoxic T-cell activity in immune-related adverse events after ICIs, we hypothesize that AIN and chronic kidney disease (CKD) that result from ICIs exist on a spectrum of T-cell mediated injury to the tubulointerstitial compartment of the kidney. In Aim 1, we will enroll 25 patients with biopsy-proved ICI-induced AIN (ICI-AIN) and 25 patients with clinically-adjudicated hemodynamic AKI after ICIs and use single-cell RNA sequencing of paired kidney biopsy tissue, blood, and urine specimens to uncover mechanisms of ICI-induced AIN. Single-cell transcriptional profiling of kidney tissue will offer insights into the cellular and molecular pathogenesis of ICI- AIN as well as a clear benchmark against which to compare blood and urine signatures (Aim 1B). We will then compare cell-based transcriptional biomarkers (Aim 1C) and cytokine biomarkers (Aim 1D) in blood and urine of patients with biopsy-proven ICI-AIN to hemodynamic AKI after ICIs to identify biomarkers unique for ICI-AIN and pathways to target in future interventional studies. In Aim 2, we will determine the relationship between ICIs and long-term kidney injury by prospectively evaluating blood and urine biomarkers of kidney injury over two years in ICI-treated patients with melanoma compared to control patients with early-stage melanoma who undergo surgical resection alone and do not receive ICIs (Aim 2A). To understand mechanisms promoting kidney function decline after ICIs, in Aim 2B, we will use scRNAseq to investigate the similarities between immune and non-immune cell transcriptional programs in blood and urine among patients with >20% eGFR decline after ICIs to patients with ICI-AIN from Aim 1B. In aggregate, the studies proposed will uncover mechanisms of ICI-induced kidney injury, have strong potential to lead to non-invasive diagnostics for ICI-AIN, and yield important biological insights into the role of T-cell disinhibition on kidney function. The proposal will capitalize on the expertise of the Severe Immunotherapy Complications Service at Massachusetts General Hospital (MGH), a first-of-its kind multidisciplinary team of oncologists and subspecialists studying immune- related adverse events, and the tremendous biobanking infrastructure of the MGH Cancer Center, driving the feasibility of these innovative aims. This Stephen I. Katz Early Stage Investigator Research Project Grant is a new direction for the principal investigator, launching a translational research program in onconephrology.