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

项目摘要 免疫检查点抑制剂（ICI）正在彻底改变癌症护理，在癌症患者中产生持久的抗肿瘤反应。 多种癌症类型;然而，通过释放T细胞应答，ICI可导致免疫相关毒性， 基本上任何器官系统，影响60-80%的受体。据保守估计， 患者在ICI后发生急性间质性肾炎（AIN），最近的一项研究发现，高达40%的患者 接受ICI后存活2年的患者将经历快速估计肾小球滤过率（eGFR）下降 （> 3 mL/min/年）。目前对ICI诱导的肾损伤的机制知之甚少， 该领域的工作是描述性的。基于已发表的研究，显示细胞毒性T细胞明显升高 活动的免疫相关不良事件后，ICI，我们假设AIN和慢性肾脏疾病， (CKD)ICIs存在于T细胞介导的肾小管间质区室损伤谱中， 肾脏在目标1中，我们将招募25例经活检证实的ICI诱导的AIN（ICI-AIN）患者和25例 ICI后临床裁定的血流动力学阿基，并使用配对肾脏的单细胞RNA测序 活检组织、血液和尿液标本，以揭示ICI诱导AIN的机制。单细胞 肾组织的转录谱分析将提供对ICI的细胞和分子发病机制的了解， AIN以及比较血液和尿液特征的明确基准（目标1B）。然后我们将 比较血液和尿液中基于细胞的转录生物标志物（Aim 1C）和细胞因子生物标志物（Aim 1D） 经活检证实的ICI-AIN患者中，有30%的患者发生了ICI后的血流动力学阿基，以确定ICI-AIN的独特生物标志物 以及未来干预性研究的靶向途径。在目标2中，我们将确定 通过前瞻性评估血液和尿液中肾损伤的生物标志物， ICI治疗的黑色素瘤患者与对照的早期黑色素瘤患者相比， 仅接受手术切除，不接受ICI（目标2A）。了解促进 在目标2B中，我们将使用scRNAseq来研究ICI后肾功能下降之间的相似性， eGFR>20%患者血液和尿液中免疫和非免疫细胞转录程序 ICI-AIN患者在ICI后从Aim 1B下降。总的来说，拟议的研究将揭示 ICI诱导的肾损伤的机制，具有很强的潜力，导致ICI-AIN的非侵入性诊断， 并对T细胞去抑制对肾功能的作用产生重要的生物学见解。该提案将 充分利用马萨诸塞州综合医院严重免疫治疗并发症服务中心的专业知识 医院（MGH），一个由肿瘤学家和研究免疫系统的亚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。这个斯蒂芬一世Katz早期研究者研究项目补助金是一个 主要研究者的新方向，启动了一个肿瘤肾脏学的转化研究项目。

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.