Tumor-specific T cell state dynamics and heterogeneity in early tumorigenesis

早期肿瘤发生中肿瘤特异性 T 细胞状态动态和异质性

基本信息

批准号：
9980808
负责人：
Andrea Schietinger
金额：
$ 63.33万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-26 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980808
关键词：
ATAC-seq Antigens CD8-Positive T-Lymphocytes CTLA4 blockade Cancer Patient Cause of Death Cells Chromatin Clinical Complex Computer Models Computing Methodologies Development Epigenetic Process Evolution Exhibits Functional disorder Gene Expression Gene Expression Profile Genetic Transcription Genomic Instability Genomics Goals Heterogeneity Human Immune Immune system Immunology Immunotherapeutic agent Immunotherapy Intervention Lesion Malignant - descriptor Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Methods Modeling Molecular Mutation NCI Center for Cancer Research Oncogenic PD-1 blockade Pathologic Patients Phase Phenotype Population Population Dynamics Solid Solid Neoplasm Specificity Stromal Cells Surface System Systems Biology T cell differentiation T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Therapeutic Intervention Time Tumor Antigens Tumor stage Work analytical tool cancer cell cancer genetics cancer genomics cancer immunotherapy carcinogenesis clinically relevant epigenomics immune checkpoint blockade imprint innovation insight mathematical model melanoma mouse model mutant neoantigens novel strategies patient subsets programmed cell death protein 1 response transcription factor transcriptome sequencing treatment response tumor tumor immunology tumor initiation tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY Project I. Tumor-specific T cell state dynamics and heterogeneity in early tumorigenesis CD8 T cells are powerful components of the immune system that have the potential to selectively eradicate cancer cells, however, in most patients, tumors progress relentlessly despite the presence of tumor-specific CD8 T cells. We developed a genetic cancer mouse model that faithfully mirrors cancer development in patients and revealed that tumor-specific CD8 T cells enter a state of dysfunction early during tumorigenesis. These T cells exhibited the hallmarks of dysfunctional T cells from late-stage human tumors. Early after tumor initiation, T cell dysfunction was plastic, but at later times, became fixed. Breakthrough therapies (immune checkpoint blockade) have emerged to reverse T cell dysfunction but these strategies have only worked in a subset of patients and a subset of tumor types. The goal of Project I is to understand the co-evolutionary cancer cell, stromal and immune population dynamics that control T cell differentiation to different functional states and consequently, T cell sensitivity to immunotherapeutic interventions. We will leverage the power of clinically-relevant genetic cancer mouse models to dissect the complex interplay of cancer genomic evolution, immune and stromal cell population dynamics, and the molecular mechanisms controlling CD8 T cell differentiation using innovative single-cell transcriptional and epigenetic analytic tools and powerful mathematical modeling approaches. In Aim 1, we will define the chromatin states and/or transcription factor networks that mediate the transition between functional, plastic dysfunctional, and fixed dysfunctional T cell states. In Aim 2, we will characterize the mutational tumor antigen landscape, stromal and immune cell population dynamics, and TCR repertoire, and build and test a mathematical model to predict how these tumor parameters determine T cell functional states. In Aim 3 we will determine whether tumor-specific T cells in human solid tumors exist in heterogeneous functional states that predict responsiveness to immune checkpoint blockade therapy. By bringing together considerable expertise in cancer immune mouse modeling, computational methods, and clinical immune checkpoint blockade therapy, these approaches will provide new insights into T cell differentiation and could novel strategies to unleash the precise power of tumor-specific CD8 T cells for cancer immunotherapy.

项目概要项目 I. 早期肿瘤发生中的肿瘤特异性 T 细胞状态动态和异质性 CD8 T 细胞是免疫系统的强大组成部分，有可能选择性地根除然而，在大多数患者中，尽管存在肿瘤特异性的癌细胞，肿瘤仍会无情地进展。 CD8 T 细胞。我们开发了一种遗传癌症小鼠模型，该模型忠实地反映了癌症的发展情况研究人员发现，肿瘤特异性 CD8 T 细胞在肿瘤发生早期就进入功能障碍状态。这些 T 细胞表现出晚期人类肿瘤功能失调的 T 细胞的特征。肿瘤发生后早期开始时，T细胞功能障碍是可塑的，但后来就变得固定了。突破性疗法（免疫检查点封锁）已经出现以逆转 T 细胞功能障碍，但这些策略仅在特定情况下有效。患者子集和肿瘤类型子集。项目 I 的目标是了解共同进化控制 T 细胞分化为不同功能的癌细胞、基质和免疫群体动态表明 T 细胞对免疫治疗干预的敏感性。我们将利用以下力量临床相关的遗传癌症小鼠模型来剖析癌症基因组进化的复杂相互作用，免疫和基质细胞群动态以及控制 CD8 T 细胞的分子机制使用创新的单细胞转录和表观遗传分析工具和强大的分化数学建模方法。在目标 1 中，我们将定义染色质状态和/或转录因子介导功能性、可塑性功能障碍和固定功能障碍 T 细胞之间转变的网络州。在目标 2 中，我们将描述突变肿瘤抗原景观、基质和免疫细胞的特征群体动态和 TCR 库，并建立和测试数学模型来预测这些肿瘤如何参数决定 T 细胞的功能状态。在目标 3 中，我们将确定肿瘤特异性 T 细胞是否存在于人类实体瘤存在异质功能状态，可预测对免疫检查点的反应封锁疗法。通过汇集癌症免疫小鼠模型方面的大量专业知识，计算方法和临床免疫检查点阻断疗法，这些方法将提供新的对 T 细胞分化的深入了解以及释放肿瘤特异性 CD8 精确能力的新策略用于癌症免疫治疗的 T 细胞。