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

• 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
• 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

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.

项目摘要 项目一肿瘤特异性T细胞在早期肿瘤发生中的状态动态和异质性 CD 8 T细胞是免疫系统的强大组成部分，具有选择性根除肿瘤的潜力。 然而，在大多数患者中，尽管存在肿瘤特异性抗体， CD 8 T细胞。我们开发了一种遗传性癌症小鼠模型，该模型忠实地反映了癌症的发展， 患者，并揭示了肿瘤特异性CD 8 T细胞在肿瘤发生早期进入功能障碍状态。 这些T细胞表现出来自晚期人类肿瘤的功能障碍性T细胞的特征。肿瘤后早期 开始时，T细胞功能障碍是可塑性的，但在以后的时间，成为固定的。突破性疗法（免疫 检查点阻断）已经出现逆转T细胞功能障碍，但这些策略仅在 患者的子集和肿瘤类型的子集。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 状态，因此，T细胞对免疫干预的敏感性。我们将利用 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， 免疫和基质细胞群体动力学，以及控制CD 8 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 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、可塑性功能障碍性和固定功能障碍性T细胞之间转变的网络 states.在目标2中，我们将描述突变的肿瘤抗原景观，基质和免疫细胞 群体动力学和TCR库，并建立和测试数学模型来预测这些肿瘤 参数决定T细胞功能状态。在目标3中，我们将确定肿瘤特异性T细胞是否在肿瘤细胞中表达。 人实体瘤以异质性功能状态存在，可预测对免疫检查点的反应性 阻断疗法通过汇集癌症免疫小鼠建模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 深入了解T细胞分化，并可能采取新的策略来释放肿瘤特异性CD 8的精确力量。 用于癌症免疫治疗的T细胞。