TOX-driven CD8 T cell differentiation and dysfunction in tumors

项目总结 在人类肿瘤中发现了针对癌细胞的CD8T细胞，但尽管存在它们，肿瘤 进展，表明T细胞变得没有反应。设计出可预见的效果 在免疫治疗方面，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 以前证明，肿瘤中的T细胞进入表观遗传编码的功能障碍状态 对治疗重新编程产生抵抗力，并发现DNA结合蛋白TOX是一个关键 执行失灵状态的监管机构。推动TOX表达的因素，以及TOX是如何 确切地建立功能障碍计划在很大程度上仍是未知的。TCR信号强度影响T 细胞分化，虽然我们知道抗原的慢性化是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驱动的 免疫治疗重编程的功能障碍和可改善性。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 临床相关遗传性肿瘤小鼠模型的建立及肿瘤进展过程中T细胞的纵向追踪 同时遇到信号强度不同的肿瘤抗原。我们将采用转录和转录技术 表观基因组学方法和创新的蛋白质降解策略，以确定什么控制TOX，如何控制TOX TOX诱导和/或维持功能障碍，以及TOX下游介体如何调节表观遗传 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- 特定的肿瘤浸润性T细胞资源，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，我们会 针对TOX和TOX下游介质改善癌症的测试和设计策略 免疫疗法。

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.