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 肾脏受损，导致死亡率显著增加。急性间质性肾炎是最常见的急性 肾脏损伤，影响2-3%接受免疫检查点抑制剂(ICIS)治疗的患者。此外，40%的 接受ICIS的肾移植患者患有急性排斥反应，一旦发生排斥反应，65%的患者会失去 同种异体移植，需要肾脏替代疗法。因此，了解ICI相关性急性胰腺炎的发病机制 肾脏损伤和寻找治疗方法至关重要。我的K08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 新抗原肽在肾脏近端小管中的特异性表达及示踪抗原特异性T细胞 四聚体染色技术检测动物的反应。结果表明，抗原的存在- 特异性T细胞和ICIS触发免疫细胞向肾脏渗透，模拟急性间质性肾炎 在接受ICIS治疗的癌症患者中可以看到。虽然动物模型是解决精确分子问题的理想选择 关于这种疾病的机制，这些发现对人类疾病的适用性是有限的。这个 我最近领导的最大规模的多中心临床研究发现，ICI相关的肾脏损伤发生得很多。 与非肾移植患者相比，肾移植受者更快、更健壮。调查结果 我的中心假设是肾移植受者中预先存在的供体抗原特异性T细胞 在ICIS存在的情况下迅速激活、增殖，并导致直接肾脏损伤。在这项初步研究中，我 建议使用人类组织样本进行高维分析，通过以下方式追踪抗原特异性T细胞 单细胞RNA测序和T细胞受体(TCR)谱分析。我们将分析TCR克隆型 和表型抗原特异性T细胞，使用存档的外周血单核细胞，肿瘤和 来自癌症ICI治疗后发生急性移植排斥反应的患者的肾活检样本，由 与达纳·费伯癌症研究所的免疫肿瘤学中心和位于 布里格姆妇女医院。这一试点项目测试了高维分析的可行性 ICI相关性肾损伤患者未来前瞻性临床试验的患者样本。如果可行， 我们将把这些分析纳入预期的临床试验中，这最终将有助于理解 癌症患者急性间质性肾炎和移植肾急性排斥反应的机制 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.