Molecular and Epigenetic Programs Underlying T cell Tolerance to Tumor Antigens

简介（由申请人提供）：Andrea Schietinger博士是一位积极进取的基础研究科学家，在肿瘤免疫学方面有很强的背景。Schietinger博士的近期目标是了解T细胞在自身抗原和肿瘤抗原特异性CD8 T细胞中无反应性的调节机制，并评估覆盖T细胞内在耐受程序的策略，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T细胞对自身抗原耐受的精确分子和表观遗传程序（K99奖励期）。从自我耐受模型中获得的见解将应用于新开发的原位实体癌模型，以了解为什么癌前病变和/或早期肿瘤中的肿瘤特异性T细胞对癌症没有反应（R00奖励期）。具体目标是：(1)通过全面、高分辨率的全基因组染色质状态分析来定义自我耐受T细胞表观基因组，并确定耐受记忆是如何编码的；(2)评估肿瘤诱导的T细胞功能障碍的功能特征，并确定肿瘤特异性T细胞的功能无应答是否是一种类似于自我耐受的印迹分化状态。(3)评估消除功能失调耐受T细胞的表观遗传记忆和永久恢复T细胞功能的策略，以用于癌症免疫治疗。阐明T细胞在不同情况下（如自身耐受和肿瘤诱导的T细胞耐受）无反应性的遗传和表观遗传调控机制可能揭示T细胞功能障碍的共同潜在原理，并为癌症和其他T细胞介导的疾病（如自身免疫和慢性感染）提供新的治疗方法。Schietinger博士将在K99奖指导期内，在华盛顿大学免疫学系教授、Fred Hutchinson癌症研究中心（FHCRC）免疫学项目负责人Philip Greenberg博士的指导下开展这项研究。格林伯格博士是小鼠和人类肿瘤免疫学领域的领先研究员，拥有成功指导的良好记录。华盛顿大学（UW）和（FHCRC）为开展拟议的研究提供了良好的环境和必要的资源，包括基础设施、人员、仪器和核心设施。Schietinger博士已经成立了一个优秀的科学顾问委员会，以确保她的学术进步，并将补充格林伯格博士的指导。委员会成员包括博士。美国华盛顿大学免疫学教授Michael Bevan；John Stamatoyannopulos，华盛顿大学基因组科学系教授；和FHCRC的成员，包括博士。Stanley Riddell，免疫学项目，Muneesh Tewari，人类生物学和临床研究部，以及Kim Margolin，医学教授（华盛顿大学）和西雅图癌症护理联盟黑色素瘤诊所负责人。所有这些成员都是各自领域的专家，将为她的项目在T细胞生物学和T细胞记忆、表观遗传学、microRNA和临床/人类肿瘤免疫学等领域带来更多的见解和技术。从长远来看，Schietinger博士的目标是成为一名肿瘤免疫学家，拥有一个独立的研究项目，利用小鼠模型来破译实体肿瘤中癌细胞和免疫细胞之间复杂的相互作用，并找到机会利用获得的见解来开发更好的人类癌症治疗方法。

DESCRIPTION (provided by applicant): 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 evaluae 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.