TOX-driven CD8 T cell differentiation and dysfunction in tumors

TOX驱动的肿瘤中CD8 T细胞分化和功能障碍

基本信息

批准号：
10586679
负责人：
Andrea Schietinger
金额：
$ 61.7万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586679
关键词：
Affinity Antigens Binding CD8-Positive T-Lymphocytes Cancer Model Cancer Patient Cell physiology Cells Chromatin Chronic DNA-Binding Proteins Data Down-Regulation Epigenetic Process Functional disorder Genetic Goals Heterogeneity Human Immune Immunotherapeutic agent Immunotherapy Maintenance Major Histocompatibility Complex Malignant Neoplasms Mediating Mediator Methods Molecular Profiling Mus Nature Peptide Receptor Phenotype Population Population Heterogeneity Receptor Signaling Repression Resistance Resources Role Signal Transduction Specificity T cell differentiation T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Tumor Antigens Tumor-Infiltrating Lymphocytes Work acute infection antigen-specific T cells cancer cell cancer genetics cancer immunotherapy cancer infiltrating T cells carcinogenesis chronic infection clinically relevant design epigenomics exhaust exhaustion genetic signature immune checkpoint blockade imprint improved innovation mouse model neoantigens novel patient subsets pharmacologic prevent programs protein degradation receptor trait transcription factor transcriptomics tumor tumor progression

项目摘要

PROJECT SUMMARY CD8 T cells specific for cancer cells are found within human tumors, but despite their presence, tumors progress, suggesting that T cells become unresponsive. To design predictably effective immunotherapies, we must elucidate the mechanisms controlling tumor-specific T cell dysfunction. We previously demonstrated that T cells in tumors enter an epigenetically encoded dysfunction state that becomes resistant to therapeutic reprogramming and found that TOX, a DNA-binding protein, is a key regulator enforcing the dysfunctional state. The factors that drive TOX expression, and how TOX precisely establishes the dysfunction program remain largely unknown. TCR signal strength impacts T cell differentiation, and while we know that antigen chronicity is a key driver of TOX-driven T cell dysfunction, we do not know how signal strength of chronic tumor antigen impacts TOX-driven dysfunction and amenability to immunotherapeutic reprogramming. In this application, we will determine how signal strength regulates TOX and TOX-driven dysfunction programs in mouse and human tumors, ask how TOX induces and maintains dysfunction, and target TOX and its downstream mediators to uncover the mechanisms underlying dysfunction imprinting. To achieve these goals, we will utilize clinically relevant genetic cancer mouse models and track T cells longitudinally within progressing tumors while encountering tumor antigens with varying signal strength. We will employ transcriptomic and epigenomic methods and innovative protein degradation strategies to determine what controls TOX, how TOX induces and/or maintains dysfunction, and how TOX downstream mediators regulate the epigenetic programs associated with plasticity and dysfunction imprinting. We will leverage human neoantigen- specific tumor-infiltrating T cell resources to understand how TCR signal strength determines TOX- dependent molecular signatures and functional states of T cells in human tumors. Importantly, we will test and design strategies to target TOX and TOX downstream mediators to improve cancer immunotherapy.

项目概要在人类肿瘤中发现了对癌细胞具有特异性的 CD8 T 细胞，但尽管存在它们，肿瘤进展，表明 T 细胞变得无反应。设计可预测的有效免疫疗法中，我们必须阐明控制肿瘤特异性T细胞功能障碍的机制。我们先前证明肿瘤中的 T 细胞进入表观遗传编码的功能障碍状态，对治疗性重编程产生抵抗力，并发现 TOX（一种 DNA 结合蛋白）是关键调节器强制执行功能失调状态。驱动 TOX 表达的因素以及 TOX 如何表达准确建立功能障碍程序仍然很大程度上未知。 TCR 信号强度影响 T 细胞分化，虽然我们知道抗原慢性是 TOX 驱动的 T 细胞的关键驱动因素功能障碍，我们不知道慢性肿瘤抗原的信号强度如何影响 TOX 驱动功能障碍和免疫治疗重编程的适应性。在此应用程序中，我们将确定信号强度如何调节小鼠和人类肿瘤中的 TOX 和 TOX 驱动的功能障碍程序，询问 TOX 如何诱导和维持功能障碍，并针对 TOX 及其下游介质揭示功能障碍印记背后的机制。为了实现这些目标，我们将利用临床相关的遗传癌症小鼠模型并在进展性肿瘤中纵向追踪 T 细胞同时遇到信号强度不同的肿瘤抗原。我们将采用转录组学和表观基因组方法和创新的蛋白质降解策略，以确定 TOX 的控制因素、控制方式 TOX 诱导和/或维持功能障碍，以及 TOX 下游介质如何调节表观遗传与可塑性和功能障碍印记相关的程序。我们将利用人类新抗原- 特定的肿瘤浸润 T 细胞资源，以了解 TCR 信号强度如何决定 TOX- 人类肿瘤中 T 细胞的依赖分子特征和功能状态。重要的是，我们将针对 TOX 和 TOX 下游介质的测试和设计策略以改善癌症免疫疗法。