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

发现 T 细胞蛋白质组更新动态以克服实体瘤微环境

基本信息

批准号：
10254806
负责人：
Brian Koss
金额：
$ 38万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-14 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10254806
关键词：
Academic Training Adoptive Cell Transfers Antigens Appointment Area Arkansas Award Biochemistry Biology Biomedical Research CD28 gene Cell Therapy Cell model Cells Centers of Research Excellence Clinical Collaborations Complex Dedications Engineering Ensure Faculty Failure Funding Grant Health Hematologic Neoplasms Hematological Disease Home Immune Immune response Immunologic Monitoring Infiltration Institutes Malignant Neoplasms Measurement Measures Medical Mentors Mentorship Molecular Biology Monitor National Institute of General Medical Sciences Nature Patient Monitoring Patients Persons Play Population Heterogeneity Positioning Attribute Principal Investigator Productivity Proteins Proteome Proteomics Publications Research Research Personnel Role Rural Savings Science Set protein Signal Pathway Solid Neoplasm Source Stress Students T-Lymphocyte Techniques Training United States National Institutes of Health Universities Vision Work adaptive immunity cancer immunotherapy cancer therapy career energy balance environmental change exhaustion experience fitness flexibility frontier innovation interest multiple omics novel novel strategies professor programs protein degradation receptor research facility response skills success tenure track therapy development transcriptome transcriptomics treatment research tumor tumor heterogeneity tumor microenvironment

项目摘要

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.

项目概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尽管过继细胞疗法在血液学治疗方面取得了成功，但仍处于癌症治疗的前沿。癌症，其有效用于对抗实体瘤的问题仍然悬而未决。由患者内部和患者内部的肿瘤异质性驱动的实体瘤生物学在很大程度上是失败的根源。需要新的方法来告知工程过继 T 细胞并监测患者的 T 细胞容量规避实体瘤中存在的多种障碍细胞动态调整蛋白质组的能力。因此，蛋白质的周转率经过优化以平衡能量。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细胞对环境变化作出反应时的途径虽然人们经常问“T 细胞如何反应”这一问题。对压力做出反应？”我们打算转变范式，提出一个根本不同的问题“T 细胞如何？为应对压力做好准备了吗？精确的蛋白质 T 细胞组依赖于确保足够的可塑性我们构思并开发了一种新颖的综合多组学技术来分析。该技术集成了蛋白质组、转录组和蛋白质动态分析。识别蛋白质“工作点”的方法，这是蛋白质动态性质的衡量标准。此前，T 细胞通过动态蛋白质组控制的适应能力决定了持久性和揭示赋予 T 细胞卓越适应性和能力的机制。此外，识别新的实体瘤将在细胞疗法的开发中具有重大的临床意义。在免疫监测中确定 T 细胞适应性的方法不仅会对癌症治疗产生影响但是，还有许多其他免疫驱动的条件，该研究的目的是 1) 定义蛋白质组更新。对共刺激和疲劳的反应发生变化，2) 操纵蛋白质周转率以增强 T 细胞持久性，以及 3) 在患者免疫监测中利用蛋白质周转率测量。