Exploiting the Mechanobiology of PD-1 for Cancer Immunotherapy

利用 PD-1 的力学生物学进行癌症免疫治疗

基本信息

批准号：
10174887
负责人：
Rafi Ahmed
金额：
$ 64.02万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
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：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10174887
关键词：
Adoptive Cell Transfers Amino Acids Antigens Binding CD28 gene CD4 Antigens CD8 receptor CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Cell Differentiation process Cell physiology Cells Chronic Communicable Diseases Complex Coupled Crystallization Cytokine Receptors Cytotoxic T-Lymphocytes DNA Data Devices Discrimination Disease Dissociation Engineering Foundations Generations Goals Human Image Immunologist Immunotherapy In Situ In Vitro Investigation Kinetics Ligands Major Histocompatibility Complex Malignant Neoplasms Mechanics Mediating Memory Methods Microfluidics Modeling Molecular Molecular Conformation Mus Mutate Oncology Peptide Receptor Peptides Receptor Signaling Regulation Reporting Signal Transduction Solid Structure T cell differentiation T cell response T cell therapy T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Thinking Tumor Immunity Vaccination Vaccine Therapy Virus Diseases acute infection adaptive immunity base cancer immunotherapy cell killing cellular imaging chemokine receptor exhaustion gp100 Antigen improved in silico in vivo insight melanoma molecular dynamics mouse model multidisciplinary novel strategies physical science programmed cell death ligand 1 programmed cell death protein 1 receptor response single molecule stem stem-like cell synergism tool tumor

项目摘要

PROJECT SUMMARY Programmed cell death 1 (PD-1) is one of the key co-inhibitory molecules upregulated upon T cell activation and is a hallmark of T-cell exhaustion. Despite the fact that PD-1 blockade has become a revolutionary strategy in treating cancer and infectious diseases, the mechanobiology of PD-1 has not been studied. This is the gap that tne present Physical Science – Oncology Project (PS-OP) aims to fill. The significance of the PS-OP’s unique mechanobiology angle lies in the therapeutic potential of targeting the mechanoregulation of PD-1 to treat a wide variety of diseases, including melanoma, which is the focus of this PS-OP. The approaches of the PS-OP’s multidisciplinary team combine four physical science (PS) tools with two mouse models of melanoma. They represent the unique strength of the Zhu lab and the Ahmed lab, and enable investigation of PD-1 mechanobiology in silico, in vitro and in vivo. The first PS tool is DNA-based mechanical tension probes (MTP) and tension gauge tethers (TGT) that report and limit, respectively, cell-generated forces on PD-1. The second PS tool is three biomembrane force probe (BFP)-based single-molecule methods that quantify force regulation of in situ PD-1–PD-ligand interactions with concurrent imaging of intracellular signals in single cells. The third PS tool is molecular dynamics (MD) simulations that reveal structural changes of PD-1 in complex with its ligands under force and the bonding dynamics at atomic level. The fourth PS-tool is microfluidic-based devices for cell trapping, stimulation, and analysis. Preliminary studies of the project demonstrate that: 1) cells actively pull on PD-1; 2) force on PD-1 elicits catch bonds to regulate ligand bonding; 3) force induces rearrangement of the PD- 1–PD-L2 binding interface to form new atomic-level interactions; 4) mutating specific amino acids on PD-1 alters its force, catch bond and function; and 5) PD-1’s inhibitory signal suppresses antigen recognition by disrupting the synergy between TCR and CD8 in pMHC binding. These data support the hypothesis that force critically regulates ligand bonding and signaling of PD-1; as such, targeting the PD-1 mechanoregulation may represent a novel approach to immunotherapy. This hypothesis will be tested by three specific aims: 1) Determine the forces on PD-1 and their impact on PD-1 ligand bonding, signaling and function; 2) Modulate T cell function by targeting PD-1 mechanoregulation; and 3) Investigate the therapeutic potential of manipulating PD-1 catch bonds in tumor mouse models. These studies will elucidate the mechanisim of PD-1 signaling, improve one’s understanding of CD8+ T-cell responses to melanoma, and suggest new immunotheraputic strategies to treating cancer.

项目概要程序性细胞死亡 1 (PD-1) 是 T 细胞激活后上调的关键共抑制分子之一，尽管 PD-1 阻断已成为 T 细胞衰竭的一个标志。在治疗癌症和传染病方面，PD-1的机制生物学尚未得到研究，这就是差距。目前的物理科学-肿瘤学项目（PS-OP）旨在填补 PS-OP 的独特意义。机械生物学的角度在于以 PD-1 的机械调节为目标来治疗广泛的疾病的治疗潜力多种疾病，包括黑色素瘤，这是本次 PS-OP 的重点。多学科团队将四种物理科学 (PS) 工具与两种黑色素瘤小鼠模型结合起来。代表了 Zhu 实验室和 Ahmed 实验室的独特优势，使 PD-1 的研究成为可能第一个 PS 工具是基于 DNA 的机械张力探针 (MTP)。和张力计系绳（TGT），分别报告和限制细胞产生的作用在 PD-1 上的力。 PS 工具是基于三种生物膜力探针 (BFP) 的单分子方法，可量化力调节原位 PD-1-PD-配体相互作用与单细胞内信号的同步成像。 PS 工具是分子动力学 (MD) 模拟，揭示 PD-1 与其配体复合物的结构变化第四种 PS 工具是基于微流体的细胞设备。该项目的初步研究表明：1）细胞主动拉动。 PD-1；2) 对 PD-1 的作用力引发捕获键以调节配体键合；3) 作用力诱导 PD- 重排； 1–PD-L2结合界面形成新的原子级相互作用4)突变PD-1上的特定氨基酸；其作用力、捕获键和功能；以及 5) PD-1 的抑制信号通过破坏来抑制抗原识别 TCR 和 CD8 在 pMHC 结合中的协同作用这些数据支持了关键的假设。调节 PD-1 的配体键合和信号传导；因此，针对 PD-1 机械调节可能代表该假设将通过三个具体目标进行检验：1）确定 PD-1 上的作用力及其对 PD-1 配体结合、信号传导和功能的影响 2) 通过调节 T 细胞功能；针对 PD-1 机械调节；3) 研究操纵 PD-1 捕获键的治疗潜力这些研究将阐明PD-1信号传导的机制，改善人们的肿瘤小鼠模型。了解 CD8+ T 细胞对黑色素瘤的反应，并提出新的免疫治疗策略癌症。