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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：
10609806
负责人：
MICHELLE KROGSGAARD
金额：
$ 55.72万
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/10609806
关键词：
Affect Affinity Antigens Antitumor Response Automobile Driving Binding Biological Assay Biological Models CD8B1 gene Cell Adhesion Cells Characteristics Chromatography Combined Modality Therapy Development Event Gene Expression Gene Expression Profile Genetic Transcription Genomics Goals In Vitro Intrinsic factor Knowledge Link Major Histocompatibility Complex Molecular Profiling Patient Isolation Patient Selection Patients Pattern Peptides Phosphorylation Population Predisposition Property Proteomics Receptor Signaling Resistance Role Sampling Selection for Treatments Signal Pathway Signal Transduction 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 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.

项目总结近年来，癌症免疫治疗取得了长足的进步，但仍需要改进的方法来在更多的患者中实现更持久的反应。抑制受体的阻断程序性死亡1(PD-1)使肿瘤反应性T细胞能够有效地识别和消除肿瘤有反应的患者亚群，但许多患者对PD-1阻断具有抵抗力。为了提高响应率，我们需要更好地了解导致治疗耐药的机制。这个项目的总体目标是是为了了解T细胞内在因素在患者反应与抵抗中的作用 PD-1封锁。我们将确定与阻断相关的信号通路和基因表达模式反应，特别关注T细胞受体(TCR)亲和力的作用。我们假设化妆肿瘤特异性T细胞TCR亲和力的改变影响肿瘤抗原识别、激活信号和下游基因表达，从而有助于患者对治疗的反应。对这些参数的分析在患者样本和小鼠模型中阻断PD-1将使我们能够识别T细胞的特性对治疗的反应。在我们的第一个目标中，我们将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细胞确定TCR亲和力如何模型会影响PD-1的阻断反应。在我们的第二个目标中，我们将使用蛋白质组和基因组分析患者抗原特异性T细胞对PD-1的全球标志性阻断反应和耐药性。在我们的第三个目的是我们将使用一组黑色素瘤患者来源的TCR，这些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。总体而言，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并将提供证据支持基于TCR亲和力的特定T细胞靶向基于TCR的联合治疗和对PD-1阻断治疗有反应的患者的选择关联性配置文件。