Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection

项目摘要 癌症免疫疗法已成为许多癌症的标准疗法。然而，它与急性 肾损伤，导致死亡率显著增加。急性间质性肾炎是最常见的急性 肾损伤，影响2-3%接受免疫检查点抑制剂（ICI）的患者。此外，40%的 接受ICIs的肾移植患者发生急性排斥反应，一旦发生排斥反应， 同种异体移植并需要肾脏替代治疗。因此，了解ICI相关急性 肾损伤和寻找治疗方法至关重要。我的K 08项目旨在了解免疫的作用， 检查点分子（PD-1和CTLA-4）在肾脏炎症中的作用， 在肾近曲小管特异性表达新抗原肽，并追踪抗原特异性T细胞 通过四聚体染色技术观察动物中的反应。结果表明，抗原的存在- 特异性T细胞和ICI触发免疫细胞浸润肾脏，模拟急性间质性肾炎 在接受ICIs治疗的癌症患者中观察到。虽然动物模型是解决精确分子问题的理想模型， 虽然疾病的机制，但这些发现对人类疾病的适用性有限。的 我最近领导的一项最大的多中心临床研究发现，ICI相关的肾损伤 与非肾移植患者相比，在肾移植受者中更快、更稳健。这些发现 我的核心假设是，肾移植受者体内预先存在的供体抗原特异性T细胞 在ICI存在时被迅速激活、增殖，并导致直接的肾损伤。在这项试点研究中，我 建议使用人体组织样本进行高维分析，以跟踪抗原特异性T细胞， 单细胞RNA测序和T细胞受体（TCR）库分析。我们将分析TCR克隆型 和抗原特异性T细胞的表型，使用存档的外周血单核细胞、肿瘤和 肾活检样本，从癌症ICI治疗后发生急性移植物排斥反应的患者中获得， 与Dana Faber癌症研究所免疫肿瘤学中心和单细胞基因组学核心合作， 布莱根妇女医院该试验项目测试了高维分析的可行性， 患者样本，用于ICI相关肾损伤患者的未来前瞻性临床试验。如果可行， 我们将在前瞻性临床试验中纳入这些分析，这将最终有助于了解 恶性肿瘤患者急性间质性肾炎和急性移植排斥反应的发生机制 免疫疗法

Project Summary Cancer immunotherapy has become a standard therapy for many cancers. However, it’s associated with acute kidney injury, resulting in significantly increased mortality. Acute interstitial nephritis is the most common acute kidney injury, affecting 2-3% of the patients receiving immune checkpoint inhibitors (ICIs). In addition, 40% of the kidney transplant patients receiving ICIs suffer from acute rejection, and once rejection occurs, 65% lose allograft and require renal replacement therapy. Thus, understanding the mechanisms of ICI-associated acute kidney injury and finding therapies is critical. My K08 project aims to understand the roles of immune checkpoint molecules (PD-1 and CTLA-4) in kidney inflammation, by using the novel animal models that express neoantigen peptides specifically in kidney proximal tubules and tracking antigen-specific T cell response in the animals by tetramer staining technique. The results showed that the presence of antigen- specific T cells and ICIs trigger the immune cell infiltration to the kidneys, mimicking acute interstitial nephritis seen in the cancer patients treated with ICIs. While animal models are ideal to address the precise molecular mechanisms of the disease, there’s a limitation in the applicability of the findings to the human disease. The largest multicenter clinical study that I led recently found that the ICI-associated kidney injury occurs much faster and more robust in kidney transplant recipients compared to non-kidney transplant patients. The findings led to my central hypothesis that pre-existing donor antigen-specific T cells in the kidney transplant recipients are quickly activated, proliferated in the presence of ICIs, and cause direct kidney injury. In this pilot study, I propose to perform high dimensional analyses using human tissue samples to track antigen-specific T cells by single cell RNA sequencing and T cell receptor (TCR) repertoire analysis. We will analyze the TCR clonotype and phenotype of antigen-specific T cells, using the archived peripheral blood mononuclear cells, tumor and kidney biopsy samples, obtained from the patients who had acute graft rejection after cancer ICI therapy, by collaborating with Center of Immuno-Oncology at Dana Faber Cancer Institute and single cell genomics core at Brigham and Women’s Hospital. This pilot project tests the feasibility of the high dimensional analysis of the patient samples for a future prospective clinical trial in the patients with ICI-associated kidney injury. If feasible, we will incorporate these analyses in the prospective clinical trial, which will eventually help understand the mechanism of acute interstitial nephritis and acute graft rejection in the patients treated with cancer immunotherapy.