Discovering T cell proteome turnover dynamics to overcome the solid tumor microenvironment

项目总结 细胞疗法是癌症免疫治疗领域的基石，许多人认为它们是下一个 癌症治疗的前沿。尽管过继细胞疗法在治疗血液病方面取得了成功 对于癌症，有效地使用它来治疗实体肿瘤的问题仍然没有解决。极其复杂的 由患者之间和患者内部的肿瘤异质性驱动的实体肿瘤生物学在很大程度上是失败的来源。 需要新的方法来通知工程采用的T细胞并监测患者的T细胞能力 以绕过实体肿瘤中存在的众多障碍。细胞动态调整蛋白质组的能力 在压力下，成分是必不可少的。出于这个原因，蛋白质周转率被优化以平衡能量- 保存稳定性和动态灵活性，作为激活或抑制信号的快速机制 细胞对环境变化作出反应的途径。虽然我们经常会问这样一个问题：T细胞是如何 对压力的反应？“我们打算将范式转变为问一个根本不同的问题：T细胞怎么样 准备好迎接压力了吗？T细胞依赖于一组精确的蛋白质来确保足够的可塑性 仍然难以捉摸。我们构思并开发了一种新的集成多组学技术来分析 蛋白质组周转动力学。这项技术集成了蛋白质组、转录组和蛋白质动态图谱 确定蛋白质“作用点”的方法，这是一种衡量蛋白质动态性质的方法。我们 假设T细胞的适应能力，通过动态蛋白质组控制，决定了持久性和 在实体瘤中发挥作用。揭示了赋予T细胞卓越的适应性和能力的机制 克服实体瘤对细胞治疗的发展具有重要的临床意义。此外，确定新的 在免疫监测中确定T细胞适合性的方法不仅对癌症的治疗有意义 但是，许多其他由免疫驱动的疾病也是如此。这项研究的目的是1)定义蛋白质组的周转 对协同刺激和疲劳的反应变化，2)操纵蛋白质周转率以增强T细胞 持久性，以及3)在患者免疫监测中使用蛋白质周转率测量。

PROJECT SUMMARY Cellular therapies are a cornerstone in the field of cancer immunotherapy, and many consider them the next frontier in cancer treatment. Despite the success of adoptive cell therapies for the treatment of hematologic cancers, the question of its effective use against solid tumors remains unresolved. The extremely complex biology of solid tumors driven by tumor heterogeneity amongst and within patients is largely the source of failure. New approaches are needed to inform the engineering adoptive T cells and to monitor a patient’s T cell capacity to circumvent the multitude of barriers present in solid tumors. The ability of a cell to dynamically adjust proteome composition is essential during stress. For that reason, protein turnover rates are optimized to balance energy- saving stability and dynamic flexibility serving as a rapid mechanism for activation or inhibition of signaling pathways when cells respond to environmental changes. While it is common to ask the question “how do T cells respond to stress?” we intend to shift the paradigm to asking a fundamentally different question “how are T cells prepared for encountering stress?” The precise set of proteins T cells depend on to ensure adequate plasticity remains elusive. We have conceived and developed a novel integrative multi-omic technique for the analysis of proteome turnover dynamics. This technique integrates proteome, transcriptome, and protein dynamic profiling approaches for the identification of protein “operating points”, a measure of protein dynamic nature. We hypothesize that the ability of a T cell to adapt, through dynamic proteome control, determines persistence and function in solid tumors. Unveiling mechanisms that endow T cells with superior adaptability and the capacity to overcome solid tumors will be of great clinical interest in cellular therapy development. Further, identifying new ways to determine T cell fitness in immune monitoring will not only have implications in the treatment of cancer but, many other immune driven conditions as well. The aims of the study are 1) Define proteome turnover changes in response to co-stimulation and exhaustion, 2) Manipulate protein turnover rates to enhance T cell persistence, and 3) Utilize protein turnover rate measurements in patient immune monitoring.