Mechanical regulation of T cell receptor and co-receptor responses in cancer immunotherapy

癌症免疫治疗中 T 细胞受体和辅助受体反应的机械调节

基本信息

批准号：
10665769
负责人：
Yuesong Hu
金额：
$ 4.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-10-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10665769
关键词：
Address Adjuvant Adoptive Cell Transfers Antigens Area Autoantigens Biological Assay CD28 gene CD80 gene Cell Adhesion Molecules Cell Size Cell Surface Receptors Cell Survival Cell membrane Cell physiology Cell surface Cells Chemicals Communication Complex Cytotoxic T-Lymphocytes DNA Discrimination Doctor of Philosophy Dose Drug Delivery Systems Drug Modulation Engineering Environment Event Flow Cytometry Fluorescence Goals Granzyme Immune Immune response Immunology Induction of Apoptosis Infusion procedures Integrins Intercellular Junctions Intercellular adhesion molecule 1 Investigation Ligands Link Lymphocyte Function Malignant Neoplasms Measurement Measures Mechanics Mediating Methods Minor Molecular Nature PLAUR gene Particle Size Patients Pattern Peptide Fragments Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Plasma Cells Postdoctoral Fellow Proliferating Proteins Research Research Project Grants Role Scanning Science Sea Seminal Signal Transduction Specificity Spectrum Analysis Speed Surface Synapses T cell regulation T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Time Tissues Touch sensation Traction Transfusion Tumor Antigens Work adaptive immune response antigen binding antigen detection cancer cell cancer immunotherapy cancer therapy chemical property cytokine cytotoxic cytotoxicity design effective therapy exhaustion fighting immune modulating agents immune reconstitution immunoengineering immunological synapse immunological synapse formation improved laser tweezer mechanical force mechanical signal mechanotransduction migration molecular mechanics mutant nanodevice optic tweezer particle perforin permissiveness physical property post-doctoral training receptor receptor binding response sensor side effect single molecule skills spatiotemporal tool tool development transmission process tumor tumor eradication unpublished works

项目摘要

PROJECT SUMMARY In the adaptive immune response, cytotoxic T lymphocyte (CTL) continuously “crawl” seeking evidence of foreign peptide fragments on the surface of other cells. Once the T cell encounters a target cell with foreign or mutant peptides, then it is activated unleashing a potent immune response. Emerging evidence suggests that cell mechanical forces transmitted to the T cell receptor (TCR) contribute to its high specificity in antigen recognition and promote T-cell activation. This is not surprising, as the TCR and other T cell co-receptors bind their cognate ligands only when two dynamic cells physically “touch”. As a first step toward understanding the role of molecular forces in tuning T cell response, it is important that we measure the magnitude of forces transmitted to ligand- receptor complexes and then to relate mechanical events to signaling and functional responses. My PhD research (F99 phase) has focused on developing methods to measure and elucidate the role of mechanical forces in immune response. I have designed a microparticle tension senor that allows one to quantify receptor forces in high throughput and also to measure forces at curved cell junctions. Additionally, I used this assay to screen the dose-response function of drugs that modulate cell mechanics. Because T cell responses are fine tuned by an array of co-receptors, I tested the role of mechanics in LFA-1 function. In this work, I demonstrated that the magnitude of LFA-1 integrin forces fine tunes TCR triggered activation and antigen discrimination. In addition, I revealed mechanically active LFA-1 defines the permissive zones for cytotoxic secretion, and suppression of LFA-1 forces significantly abrogates cytotoxicity. My work suggests that receptors cooperate to tune T-cell responses. For the remainder of my F99 phase, I will investigate the mechano-communication between receptor forces. Specifically, I will develop a DNA origami nano device to pattern ligands and measure spatiotemporal colocalization of mechanical events. Afterwards, I will proceed to test this hypothesis on cell plasma membrane by engineering tension probes on the surface of living cells. This will enable one to control and measure TCR-forces at authentic cell-cell junctions that mimic the chemical and physical properties of the immune synapse. For my postdoctoral work (K00 phase), I aim to improve upon current cancer therapies by leveraging T cell mechanics in boosting the specificity of immune response. In adoptive cell therapy (ACT), after therapeutic T-cell reinfusion, adjuvant drugs such as cytokines need to be administered to boost immune reconstitution. However, nonspecific drug release causes side effects and T-cell exhaustion. To address this challenge, I will decorate T-cells with DNA cages that mechanically trigger the release of encapsuled drugs at the tumor zone. If successful, this work will significantly enhance the ACT efficiency and offer the first example that links mechanobiology to cancer immunotherapy.

项目摘要在适应性免疫响应中，细胞毒性T淋巴细胞（CTL）继续“爬行”，寻求外国的证据其他细胞表面上的肽片段。一旦T细胞遇到具有外国或突变体的目标细胞肽，然后被激活释放潜在的免疫响应。新兴证据表明细胞传播到T细胞受体（TCR）的机械力在抗原识别中有助于其高特异性并促进T细胞激活。这并不奇怪，因为TCR和其他T细胞共受体结合其同源仅当两个动态细胞在物理上“触摸”时，配体。作为理解分子作用的第一步调整T细胞反应的力，重要的是要测量传递给配体的力的大小受体复合物，然后将机械事件与信号传导和功能响应相关联。我的博士研究（F99阶段）致力于开发衡量和阐明的作用的方法免疫响应中的机械力。我设计了一个微颗粒张力剂，可以量化高吞吐量的受体力量，并在弯曲的细胞连接处测量力。另外，我用了测定调节细胞力学的药物的剂量反应功能。因为T细胞反应通过一系列共受体调节，我测试了力学在LFA-1功能中的作用。在这项工作中，我证明LFA-1整联蛋白的大小力量微调TCR触发了激活和抗原歧视。此外，我揭示了机械活性的LFA-1定义了细胞毒性的允许区域分泌和抑制LFA-1力显着消除了细胞毒性。我的工作表明接收器协调调整T细胞响应。在我的F99阶段的其余部分中，我将研究受体力之间的机械通信。具体来说，我将发展一个DNA折纸纳米装置以模拟配体和测量机械事件的时空共定位。之后，我将继续通过工程张力问题在细胞质膜上检验这一假设活细胞。这将使人们能够在真实的细胞 - 细胞连接处控制和测量TCR-Forces，以模仿免疫非吸管的化学和物理特性。对于我的博士后工作（K00阶段），我的目标是通过利用T来改善当前的癌症疗法在增强免疫反应的特异性方面的细胞力学。在治疗后自适应细胞疗法（ACT） T细胞再灌注，可调节的药物（例如细胞因子）需要施用以增强免疫重建。但是，非特异性药物释放会导致副作用和T细胞疲劳。为了应对这一挑战，我将用DNA笼子装饰T细胞，该蛋白笼可以机械地触发肿瘤区域封装药物的释放。如果成功，这项工作将大大提高行动效率，并提供第一个链接的示例癌症免疫疗法的机械生物学。