Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens

T 细胞对肿瘤抗原耐受的分子和表观遗传程序

• 批准号: 9205491
• 负责人: Andrea Schietinger
• 金额: $ 24.9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205491
• 关键词: Advisory Committees; Antigen Targeting; Antigens; Area; Autoantigens; Autoimmune Process; Autoimmunity; Award; Basic Science; CD8-Positive T-Lymphocytes; Cancer Model; Cell Cycle; Cell physiology; Cells; Cellular biology; Characteristics; Chromatin; Chronic; Clinic; Clinical; Clinical Research; Committee Members; Complement; Complex; Core Facility; Data; Development; Disease; Environment; Epigenetic Process; Fred Hutchinson Cancer Research Center; Functional disorder; Genes; Genetic; Genome; Goals; Head; Human; Human Biology; Human Resources; Immune; Immune response; Immune system; Immunologist; Immunology; Infection; Injury; Lead; Lesion; Lymphopenia; Malignant Neoplasms; Mediating; Medicine; Memory; Mentors; Mentorship; Messenger RNA; MicroRNAs; Microtus; Modeling; Molecular; Mutate; Nature; Patients; Premalignant; Proliferating; Proteins; Public Health; Research; Research Infrastructure; Research Personnel; Resolution; Resources; Science; Scientist; Self Tolerance; Signal Pathway; Solid; Solid Neoplasm; Stimulus; T cell differentiation; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; Technology; Tolerogen; Tumor Antigens; Universities; Viral; Washington; Work; cancer care; cancer cell; cancer immunotherapy; cancer therapy; clinically relevant; design; epigenetic memory; epigenome; functional disability; genetic signature; genome-wide; genome-wide analysis; immunogenic; imprint; improved; insight; instrumentation; melanoma; member; mouse model; novel therapeutic intervention; permissiveness; prevent; professor; programs; response; success; tumor; tumor immunology

PROJECT SUMMARY / ABSTRACT Dr. Andrea Schietinger is a motivated basic research scientist with a strong background in tumor immunology. Dr. Schietinger's immediate goals are to understand the regulatory mechanism(s) of T cell unresponsiveness in self-antigen and tumor-antigen specific CD8 T cells and evaluate strategies to override T cell-intrinsic tolerance programs to improve cancer immunotherapy. Dr. Schietinger will use clinically relevant mouse models to elucidate the precise molecular and epigenetic programs underlying T cell tolerance to self-antigens (K99 award period). Insights gained from the self-tolerance model will then be applied to a newly developed autochthonous solid cancer model to understand why tumor-specific T cells in premalignant lesions and/or early tumors become unresponsive to the cancer (R00 award period). The Specific Aims are: (1) To define the self-tolerant T cell epigenome through comprehensive, high-resolution genome-wide analysis of chromatin states and to determine how tolerance memory is encoded, (2) To evaluate the functional characteristics of tumor-induced T cell dysfunction and to determine if functional unresponsiveness of tumor-specific T cells is an imprinted differentiation state similar to self-tolerance, and (3) To evaluate strategies to erase the epigenetic memory in dysfunctional tolerant T cells and to permanently rescue T cell function for cancer immunotherapy. Elucidating the genetic and epigenetic regulatory mechanism(s) of T cell unresponsiveness in different settings such as self-tolerance and tumor- induced T cell tolerance may reveal common underlying principles of T cell dysfunction and lead to new therapeutic approaches for cancer and other T cell-mediated diseases such as autoimmunity and chronic infections. Dr. Schietinger will carry out the research during the mentored K99 award period under the guidance of Dr. Philip Greenberg, Professor in the Department of Immunology, University of Washington, and Head of the Program of Immunology, Fred Hutchinson Cancer Research Center (FHCRC). Dr. Greenberg is a leading researcher in the field of mouse and human tumor immunology with a proven track record of successful mentorship. The University of Washington (UW) and (FHCRC) provide an excellent environment with the necessary resources, including infrastructure, personnel, instrumentation and core facilities, to carry out the proposed studies. Dr. Schietinger has formed an excellent scientific advisory committee that assures her academic progress and will complement Dr. Greenberg's mentorship. The committee members include Drs. Michael Bevan, Professor in the Department of Immunology (UW); John Stamatoyannopulos, Professor in the Department of Genome Sciences (UW); and Members of the FHCRC including Drs. Stanley Riddell, Program of Immunology, Muneesh Tewari, Human Biology and Clinical Research Division, and Kim Margolin, Professor of Medicine (UW) and Head of the Melanoma Clinic at the Seattle Cancer Care Alliance. All of these members are experts in their fields and will bring additional insights and technologies to her project in the areas of T cell biology and T cell memory, epigenetics, microRNA, and clinical/human tumor immunology. In the long-term, Dr. Schietinger's goal is to become a tumor immunologist with an independent research program using mouse models to decipher the complex interplay between cancer cells and immune cells in solid tumors and find opportunities to use the acquired insights to develop better treatments for human cancers.

项目摘要/摘要 Andrea Schietinger博士是一位积极的基础研究科学家，具有强大的肿瘤背景 免疫学Schietinger博士的近期目标是了解T细胞的调节机制。 自身抗原和肿瘤抗原特异性CD 8 T细胞的无反应性，并评估超越T细胞的策略。 细胞内在耐受性计划，以改善癌症免疫治疗。 Schietinger博士将使用临床相关的小鼠模型来阐明精确的分子和 表观遗传程序是T细胞对自身抗原耐受性的基础（K99奖励期）。从《世界人权宣言》中获得的见解 然后将自身耐受模型应用于新开发的本地实体癌模型， 理解为什么癌前病变和/或早期肿瘤中的肿瘤特异性T细胞对化疗无反应， 癌症（R 00奖励期）。具体目的是：（1）确定自我耐受T细胞表观基因组， 全面的，高分辨率的全基因组染色质状态分析，并确定如何耐受 （2）评价肿瘤诱导的T细胞功能障碍的功能特征， 确定肿瘤特异性T细胞的功能性无反应性是否是类似于 自身耐受性，以及（3）评估消除功能失调的耐受性T细胞中的表观遗传记忆的策略 并永久性地挽救T细胞功能用于癌症免疫治疗。阐明遗传和表观遗传 T细胞无反应性在不同环境中的调节机制，如自身耐受和肿瘤- 诱导的T细胞耐受可能揭示了T细胞功能障碍的共同基本原理，并导致新的免疫缺陷。 用于癌症和其它T细胞介导的疾病（例如自身免疫和慢性炎症）的治疗方法 感染. Schietinger博士将在指导K99奖期间在以下人员的指导下进行研究： 博士Philip Greenberg，华盛顿大学免疫学系教授， 弗雷德哈钦森癌症研究中心（FHCRC）免疫学项目。格林伯格博士是一位 小鼠和人类肿瘤免疫学领域的研究人员，具有成功的 导师制华盛顿大学（UW）和（FHCRC）提供了一个良好的环境， 必要的资源，包括基础设施、人员、仪器和核心设施，以开展 建议的研究。Schietinger博士组建了一个优秀的科学顾问委员会， 学术进步，并将补充格林伯格博士的导师。委员会成员包括Dr. Michael Bevan，免疫学系教授（UW）; John Stamatoyannopulos，免疫学系教授 基因组科学系（UW）和FHCRC成员，包括Stanley里德尔博士，计划 人类生物学和临床研究部Muneesh Tewari和Kim Margolin教授 医学博士（UW）和西雅图癌症护理联盟黑色素瘤诊所负责人。所有这些成员 是各自领域的专家，将为她在T细胞领域的项目带来更多的见解和技术。 生物学和T细胞记忆，表观遗传学，microRNA和临床/人类肿瘤免疫学。 从长远来看，Schietinger博士的目标是成为一名肿瘤免疫学家， 使用小鼠模型来破译癌细胞和免疫系统之间复杂的相互作用的研究计划 研究实体瘤中的细胞，并找到机会利用获得的见解为人类开发更好的治疗方法。 癌的

项目成果

TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion.

• DOI: 10.1084/jem.20201966
• 发表时间: 2022-02-07
• 期刊: The Journal of experimental medicine
• 作者: Shakiba M;Zumbo P;Espinosa-Carrasco G;Menocal L;Dündar F;Carson SE;Bruno EM;Sanchez-Rivera FJ;Lowe SW;Camara S;Koche RP;Reuter VP;Socci ND;Whitlock B;Tamzalit F;Huse M;Hellmann MD;Wells DK;Defranoux NA;Betel D;Philip M;Schietinger A
• 通讯作者: Schietinger A

Beyond Genomics: Multidimensional Analysis of Cancer Therapy Resistance.

超越基因组学：癌症治疗耐药性的多维分析。

• DOI: 10.1016/j.it.2015.09.003
• 发表时间: 2015
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Philip,Mary;Schietinger,Andrea
• 通讯作者: Schietinger,Andrea