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

项目摘要 细胞疗法是癌症免疫疗法领域的基石，许多人认为它们是下一个 癌症治疗的前沿尽管过继性细胞疗法在治疗血液病方面取得了成功， 尽管它被用于治疗癌症，但其对实体瘤的有效使用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瘤生物学主要是失败的根源。 需要新的方法来指导工程过继性T细胞并监测患者的T细胞能力 以避开实体瘤中存在的众多屏障。细胞动态调节蛋白质组的能力 在压力下，合成物是必不可少的。因此，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传导的快速机制 当细胞对环境变化做出反应时。虽然人们常问这样一个问题：“T细胞如何 对压力的反应？”我们打算改变范式，提出一个根本不同的问题， 准备好面对压力了吗”T细胞所依赖的一组精确的蛋白质以确保足够的可塑性 仍然难以捉摸我们已经构思并开发了一种新的综合多组学技术，用于分析 蛋白质组周转动力学。该技术集成了蛋白质组、转录组和蛋白质动态分析 用于识别蛋白质“操作点”的方法，蛋白质动态性质的量度。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， 在实体瘤中的作用。揭示了赋予T细胞上级适应性和 克服实体瘤将在细胞疗法开发中具有巨大的临床意义。此外，确定新的 在免疫监测中确定T细胞适应性的方法不仅对癌症的治疗有意义， 但也有许多其他的免疫驱动条件。本研究的目的是：1）定义蛋白质组转换 对共刺激和耗竭的反应变化，2）操纵蛋白质周转率以增强T细胞 持久性，和3）在患者免疫监测中利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.