Spatiotemporal regulation of T cell fate decisions in cancer

癌症中 T 细胞命运决定的时空调控

• 批准号: 9350820
• 负责人: Andrea Schietinger
• 金额: $ 257.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350820
• 关键词: Address; Antigens; Automobile Driving; CD8-Positive T-Lymphocytes; Cancer Cell Growth; Cancer Control; Cells; Chromatin; Development; Excision; Goals; Immune system; Immunosuppressive Agents; Malignant Neoplasms; Maps; Mutate; Normal tissue morphology; Pathologic; Patients; Premalignant; Proteins; Shapes; Signal Transduction; Solid Neoplasm; Stem cells; T cell differentiation; T cell regulation; T-Lymphocyte; Technology; Testing; Tissues; Tumor Antigens; cancer cell; cancer genetics; cancer immunotherapy; clinically relevant; design; epigenome; exhaust; fighting; immunopathology; insight; mouse model; novel; pathogen; spatiotemporal; tumor; tumorigenesis

PROJECT SUMMARY The immune system has enormous power to detect and eliminate pathogens; however, harnessing this power to fight cancer has proven challenging. A major barrier is that CD8 T cells specific for tumor-specific (mutated) proteins and found in tumors are non-responsive and fail to eliminate cancer cells. This non-responsive state has been thought to arise late during tumor development because tumor-specific T cells become “exhausted” and derailed from their normal effector programming by persistent antigen exposure and/or immunosuppressive microenvironmental factors. Using clinically-relevant genetic cancer mouse models, I recently demonstrated that tumor-specific T cells differentiate to a non-responsive state at the pre-malignant stage, long before the emergence of a pathologically-defined tumor. Thus, T cell non-responsiveness is not necessarily established late during tumorigenesis, but instead already after the initial encounters with tumor antigen. Therefore, to reprogram tumor-specific T cells for cancer immunotherapy, we must look beyond the current framework of tumor-specific T cells as “exhausted” effectors that need to be re-invigorated and instead design strategies to re-differentiate tumor-specific T cells out of the non-responsive fate to a functional state. In this proposal, I plan to address three critical questions: (1) When and where are tumor-specific T cells fate decisions made? Do signals received during the initial encounter with tumor antigen determine cell fates? (2) How do tumor-specific T cell states in different compartments evolve after tumor resection? Is tumor-specific T cells fate fixed, or can it evolve or change with tumor removal? (3) How can we effectively reprogram tumor- specific T cells for the treatment of solid tumors? To achieve this goal, I propose to (i) map the temporal and spatial factors shaping tumor-specific T cells fate decisions during tumorigenesis (ii) determine the plasticity and chromatin states of tumor-specific T cells in different tissue compartments before and after tumor resection and (iii) use insights gained from stem cell reprogramming studies together with novel epigenome editing technology to re-differentiate tumor-specific T cells that will allow them to effectively control cancer cell growth without inducing excessive immunopathology.

项目摘要 免疫系统具有巨大的检测和消除病原体的能力。但是，利用这种力量 与癌症作斗争已被证明是挑战。一个主要的障碍是CD8 T细胞针对肿瘤特异性（突变） 蛋白质并在肿瘤中发现的蛋白质无反应性，无法消除癌细胞。这种无反应状态 人们认为肿瘤特异性T细胞“耗尽”，因此被认为是在肿瘤发育后期出现的 并通过持续的抗原暴露和/或从其正常效应子编程中脱轨 免疫抑制微环境因素。使用与临床上相关的遗传癌小鼠模型，I 最近证明，肿瘤特异性T细胞在预防剂处分化为无反应状态 阶段，早在病理定义的肿瘤出现之前。那是T细胞无反应性不是 在肿瘤发生期间必须建立后期，但在与肿瘤的初始相遇之后已经建立 抗原。因此，要重新编程肿瘤特异性T细胞进行癌症免疫疗法，我们必须超越 当前的肿瘤特异性T细胞框架是“耗尽”的效果，需要重新感染，而是 将肿瘤特异性T细胞从非反应性命运中重新分化为功能状态的设计策略。 该提议，我计划解决三个关键问题：（1）肿瘤特异性T细胞何时何地 决定？在与肿瘤抗原初次相遇期间收到的信号是否确定细胞命运？ （2） 肿瘤切除后不同隔室中的肿瘤特异性T细胞状态如何？是肿瘤特异性t 细胞命运固定，还是可以通过切除肿瘤而发展或变化？ （3）我们如何有效地重新编程肿瘤 特定的T细胞用于治疗实体瘤？为了实现这一目标，我建议（i）绘制临时性和 肿瘤发生过程中塑造肿瘤特异性T细胞脂肪决策的空间因素（II）决定了可塑性 肿瘤切除前后不同组织室中肿瘤特异性T细胞的染色质状态 （iii）使用从干细胞重编程研究中获得的见解以及新型表观基因组编辑 重新分化肿瘤特异性T细胞的技术，该细胞将使它们有效控制癌细胞生长 没有诱导过多的免疫病理学。