A systematic approach to uncover the basic mechanisms of checkpoint inhibitor immune related adverse events

揭示检查点抑制剂免疫相关不良事件基本机制的系统方法

基本信息

  • 批准号:
    10637272
  • 负责人:
  • 金额:
    $ 73.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-20 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Immune checkpoint inhibitors (ICIs) have profoundly altered cancer treatment. However, despite this technique’s success, there remain major challenges to ICIs use that must be met to best advance these therapies. These include increasing responsiveness to PD-1 and CTLA-4 blockade, uncovering new targets to optimize pathway blockade and addressing why more than one third of all patients that receive ICIs develop often devastating immune related adverse events (irAEs) syndromes characterized by various patterns of off-target organ inflammation. There is currently no clear understanding of the complexity and heterogeneity of irAEs and as ICIs approaches are expanded, understanding the basic mechanisms of irAEs stands to be a critical goal. We hypothesize that three distinguishable, but not mutually exclusive, pathogenic processes drive irAEs, and that the contribution of each varies according to the type of the irAEs. The first process is not tumor-related and is predetermined by known T cell autoimmune susceptibility genes, reflecting a failure of the negative selection mechanism. However, progression to an autoimmune disease is held in a latent preclinical stage by peripheral tolerance mechanisms until triggered by the inhibition of these mechanisms through ICIs. We hypothesize that the second process driving irAEs is an intrinsic consequence of the T cell immune response directed to tumor antigens. We envision that some of the TCR clonotypes responding directly to the tumor are specific for a peptide that is also expressed by target organ MHC molecules involved in the irAEs, and that activation of this expanded clone by ICIs initiates its attack on the tumor and on the target tissue, resulting in irAEs. Finally, since many of the tumor-infiltrating lymphocytes are not clonal, we hypothesize a third process of irAEs wherein the inflammatory response is mediated by promiscuous nonspecific TCR clones activated by ICIs or the tumor inflammatory milieu. Aim 1. To characterize the human T cell repertoire of irAEs patients. We will perform a gDNA repertoire analysis and single cell TCR seq of T cells isolated from the blood, synovial fluid, and synovial tissue of patients with irAEs, to uncover the physical-chemical properties of CDR3s in comparison to T cells that mediate other autoimmune diseases. We will take advantage of the gDNA to test the hypothesis that the entrance of these self-reactive TCRs in a patient’s repertoire is influenced by the variants of the same non-HLA alleles associated with other autoimmune disease susceptibility and the failure of negative selection and examine the role of the MHC allotype on repertoire selection and irAEs development. We will use humanized immune system mice to recreate, from hemopoietic stem cells, a replica of the irAEs patients’ pre-ICIs and pre-tumor TCR repertoire, to study repertoire evolution. Aim 2. To immunophenotype the irAEs mouse model. We developed a novel mouse model for ICIs-induced adverse events. We will perform CITEseq of T cells isolated from tumors and inflamed organs to uncover differential subsets of cells and their functions across different types of tumors. Through tetramer staining and TCRseq, we will uncover the contribution of tumor-specific T cells to the pathogenesis of irAEs. We will utilize multiplex IF studies to uncover the contribution of the tumor and the inflamed organ microenvironment to the function of the infiltrating cells.
摘要 免疫检查点抑制剂(ICI)已经深刻地改变了癌症治疗。然而,尽管这项技术取得了成功, 但是对于ICI的使用仍然存在着重大的挑战,必须应对这些挑战以最好地推进这些疗法。其中包括增加 对PD-1和CTLA-4阻断的反应性,发现新的靶点以优化通路阻断并解决原因 超过三分之一的接受ICI的患者经常发生破坏性的免疫相关不良事件(irAE) 以各种非靶器官炎症模式为特征的综合征。目前还没有明确的认识 irAE的复杂性和异质性,以及随着ICI方法的扩展,了解其基本机制 是一个关键目标。我们假设三种可区分但不相互排斥的致病性 过程驱动irAE,并且每个过程的贡献根据irAE的类型而变化。第一个过程不是 肿瘤相关的,是由已知的T细胞自身免疫易感基因,反映了失败的阴性 选择机制然而,外周免疫系统将自身免疫性疾病的进展控制在潜在的临床前阶段, 耐受机制,直到通过ICI抑制这些机制而触发。我们假设第二个 驱动irAE的过程是针对肿瘤抗原的T细胞免疫应答的内在结果。我们设想 一些直接响应肿瘤的TCR克隆型对也由靶细胞表达的肽具有特异性, 免疫组织化学研究表明,扩增的克隆被ICIs激活,启动了对免疫缺陷病毒的攻击。 肿瘤和靶组织上,导致irAE。最后,由于许多肿瘤浸润淋巴细胞不是克隆的, 我们假设irAE的第三个过程,其中炎症反应由混杂的非特异性TCR介导, 由ICI或肿瘤炎性环境激活的克隆。目标1.表征irAE的人T细胞库 患者我们将对从血液、滑膜、淋巴细胞和淋巴细胞中分离的T细胞进行gDNA库分析和单细胞TCR测序。 irAE患者的体液和滑膜组织,以揭示与T 介导其他自身免疫性疾病的细胞。我们将利用gDNA来检验以下假设: 这些自身反应性TCR进入患者的库受相同非HLA等位基因的变体的影响 与其他自身免疫性疾病易感性和阴性选择失败相关,并研究其作用。 MHC同种异型对库选择和irAE发展的影响。我们将使用人源化免疫系统小鼠来重现, 从造血干细胞(irAE患者的ICI前和肿瘤前TCR库的复制品)到研究库 进化目标2.对irAE小鼠模型进行免疫表型分析。我们开发了一种新的ICIs诱导的小鼠模型, 不良事件。我们将对从肿瘤和炎症器官中分离的T细胞进行CITEseq,以揭示差异化的 细胞亚群及其在不同类型肿瘤中的功能。通过四聚体染色和TCRseq, 揭示肿瘤特异性T细胞对irAE发病机制的贡献。我们将利用多重IF研究, 揭示肿瘤和发炎器官微环境对浸润细胞功能的贡献。

项目成果

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Adam Mor其他文献

Adam Mor的其他文献

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{{ truncateString('Adam Mor', 18)}}的其他基金

PAG is a novel target in immunotherapy
PAG是免疫治疗的新靶点
  • 批准号:
    10265559
  • 财政年份:
    2020
  • 资助金额:
    $ 73.77万
  • 项目类别:
PAG is a novel target in immunotherapy
PAG是免疫治疗的新靶点
  • 批准号:
    10120348
  • 财政年份:
    2020
  • 资助金额:
    $ 73.77万
  • 项目类别:
PAG is a novel target in immunotherapy
PAG是免疫治疗的新靶点
  • 批准号:
    10458108
  • 财政年份:
    2020
  • 资助金额:
    $ 73.77万
  • 项目类别:
PAG is a novel target in immunotherapy
PAG是免疫治疗的新靶点
  • 批准号:
    10684896
  • 财政年份:
    2020
  • 资助金额:
    $ 73.77万
  • 项目类别:
(PQ8) Predictive biomarkers for the onset of immune-related adverse events associated with PD-1 blockade
(PQ8) 与 PD-1 阻断相关的免疫相关不良事件发生的预测生物标志物
  • 批准号:
    9806456
  • 财政年份:
    2019
  • 资助金额:
    $ 73.77万
  • 项目类别:
Novel mechanisms regulating PD-1 signaling and function
调节 PD-1 信号传导和功能的新机制
  • 批准号:
    10522391
  • 财政年份:
    2016
  • 资助金额:
    $ 73.77万
  • 项目类别:
Novel mechanisms regulating PD-1 signaling and function
调节 PD-1 信号传导和功能的新机制
  • 批准号:
    10628041
  • 财政年份:
    2016
  • 资助金额:
    $ 73.77万
  • 项目类别:
Novel mechanisms regulating PD-1 signaling and function
调节 PD-1 信号传导和功能的新机制
  • 批准号:
    9158876
  • 财政年份:
    2016
  • 资助金额:
    $ 73.77万
  • 项目类别:

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降低儿童和青少年高风险药物的儿科不良事件风险:提高牙科诊所中儿科患者的安全
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