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：
10737760
负责人：
Rafi Ahmed
金额：
$ 7.9万
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/10737760
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 Cytokine Receptors Cytotoxic T-Lymphocytes DNA Data Devices Discrimination Disease Dissociation Effector Cell Engineering Foundations Generations Goals Human Image Immunologist Immunooncology 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 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.

项目摘要程序性细胞死亡1（PD-1）是T细胞激活和是T细胞耗尽的标志。尽管PD-1封锁已成为革命性的策略治疗癌症和传染病，PD-1的机制尚未研究。这是一个差距目前的物理科学 - 肿瘤学项目（PS-OP）旨在填补。 PS-OP独特的意义机械生物学角度在于靶向PD-1的机械调节以治疗较宽的治疗潜力多种疾病，包括黑色素瘤，这是该PS-OP的重点。 PS-OP的方法多学科团队将四种物理科学（PS）工具与两个黑色素瘤的老鼠模型相结合。他们代表朱实验室和艾哈迈德实验室的独特强度，并可以研究PD-1 计算机，体外和体内的机械生物学。第一个PS工具是基于DNA的机械张力探针（MTP）分别报告和限制的PD-1细胞产生的力分别报告和限制。第二个 PS工具是三个基于生物膜力探针（BFP）的单分子方法，可量化力调节与单个细胞中细胞内信号的同时成像的原位PD-1 – PD-配合相互作用的相互作用。第三 PS工具是分子动力学（MD）模拟，揭示了PD-1与配体配合物中的结构变化在原子水平的力和粘结动力下。第四个PS-Tool是基于微流体的电池设备捕获，刺激和分析。该项目的初步研究表明：1）细胞主动进行 PD-1; 2）PD-1上的力引起键入键以调节配体键合； 3）力诱导Pd-重新排列 1 – PD-L2结合界面形成新的原子级相互作用； 4）在PD-1上突变特异性氨基酸变化它的力量，关键和功能； 5）PD-1的抑制信号通过破坏抑制抗原识别 PMHC结合中TCR和CD8之间的协同作用。这些数据支持了批判性的假设调节PD-1的配体键合和信号传导；因此，针对PD-1机械调节可能代表一种新型免疫疗法的方法。该假设将通过三个特定目的测试：1）确定 PD-1上的力及其对PD-1配体键，信号传导和功能的影响； 2）通过靶向PD-1机械调节； 3）研究操纵PD-1捕获键的治疗潜力在肿瘤小鼠模型中。这些研究将阐明PD-1信号的机械印象，改善一个人了解CD8+ T细胞对黑色素瘤的反应，并建议治疗新的免疫疗法策略癌症。