T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

T 细胞抵抗 PD-1 检查点阻断的内在机制

基本信息

批准号：
10524151
负责人：
MICHELLE KROGSGAARD
金额：
$ 7.22万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10524151
关键词：
Affect Affinity Antigens Antitumor Response Automobile Driving Binding Biological Assay CD8B1 gene Cell Adhesion Cell model Cells Characteristics Chromatography Combined Modality Therapy Development Event Gene Expression Gene Expression Profile Genetic Transcription Genomics Goals In Vitro Intrinsic factor Knowledge Lead Link Major Histocompatibility Complex Molecular Profiling Optimum Populations Patient Isolators Patient Selection Patients Pattern Peptides Phosphorylation Population Property Proteomics Receptor Signaling Resistance Role Sampling Selection for Treatments Signal Transduction Signaling Protein Stains T cell response T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Tumor Antigens Tumor-Infiltrating Lymphocytes Work antigen-specific T cells base cancer immunotherapy cancer therapy cross reactivity effective therapy experimental study humanized mouse immune checkpoint blockade improved in vivo melanoma mouse model new technology novel patient response potential biomarker predictive marker programmed cell death ligand 1 programmed cell death protein 1 receptor receptor binding resistance mechanism response therapy resistant transcriptomics treatment optimization treatment response tumor unnecessary treatment

项目摘要

PROJECT SUMMARY Cancer immunotherapy has made great strides in recent years, yet improved approaches are required to achieve more durable responses in a greater number of patients. Blockade of the inhibitory receptor programmed-death 1 (PD-1) enables tumor-reactive T cells to effectively recognize and eliminate tumors in a subset of responsive patients, but many patients are resistant to PD-1 blockade. To improve response rates, we need to better understand the mechanisms that lead to therapeutic resistance. The overall goal of this project is to understand the role of T cell–intrinsic factors that contribute to patient response versus resistance to PD-1 blockade. We will identify signaling pathways and gene-expression patterns associated with blockade response with a particular focus on the role of T-cell receptor (TCR) affinity. We hypothesize that the make-up of TCR affinities of tumor-specific T cells affects tumor antigen recognition, activation signaling, and downstream gene expression, thus contributing to patient response to therapy. Analysis of these parameters in patient samples and mouse models of PD-1 blockade will allow us to identify T cell properties characteristic of response to therapy. In our first aim we will isolate and quantify the TCR-binding properties of melanoma antigen-specific T cells from PD-1 blockade–responsive and –resistant patients to determine how TCR affinity profiles influence PD-1 blockade responses. In our second aim we will use proteomic and genomic analysis of patient antigen-specific T cells to develop a global signature of PD-1 blockade response and resistance. In our third aim we will use a panel of melanoma patient–derived TCRs with varying affinities for the same antigen for in vitro and in vivo experiments to determine how TCR affinity influences response to PD-1 blockade. Overall, we will determine the contribution of TCR affinities of melanoma-specific T cells to blockade resistance and will provide evidence to support the targeting of specific T cells based on TCR affinity for combination therapies and the selection of patients likely to respond to PD-1 blockade therapy based on TCR affinity profiles.

项目概要近年来，癌症免疫疗法取得了长足的进步，但仍需要改进的方法在更多患者中获得更持久的反应。程序性死亡 1 (PD-1) 使肿瘤反应性 T 细胞能够有效识别并消灭肿瘤部分有反应的患者，但许多患者对 PD-1 阻断具有抵抗力。为了提高反应率，我们进行了研究。需要更好地了解导致治疗耐药的机制。该项目的总体目标。的目的是了解 T 细胞内在因素的作用，这些因素有助于患者的反应与耐药性我们将识别与阻断相关的信号通路和基因表达模式。我们特别关注 T 细胞受体 (TCR) 亲和力的作用。肿瘤特异性 T 细胞的 TCR 亲和力影响肿瘤抗原识别、激活信号传导和下游基因表达，从而有助于分析这些参数的患者反应。在患者样本和小鼠模型中，PD-1 阻断将使我们能够识别 T 细胞的特性特征我们的第一个目标是分离和量化黑色素瘤的 TCR 结合特性。来自 PD-1 阻断反应和耐药患者的抗原特异性 T 细胞，以确定 TCR 亲和力如何配置文件影响 PD-1 阻断反应在我们的第二个目标中，我们将使用蛋白质组学和基因组分析。患者抗原特异性 T 细胞产生 PD-1 阻断反应和耐药性的全局特征。第三个目标，我们将使用一组源自黑色素瘤患者的 TCR，对同一抗原具有不同的亲和力用于体外和体内实验，以确定 TCR 亲和力如何影响对 PD-1 阻断的反应。总的来说，我们将确定黑色素瘤特异性 T 细胞的 TCR 亲和力对阻断的贡献耐药性，并将提供证据支持基于 TCR 亲和力的特定 T 细胞的靶向联合疗法以及根据 TCR 选择可能对 PD-1 阻断疗法有反应的患者亲和力概况。