Identify receptors for B7 family immune checkpoint orphan ligands using a novel cellbased approach

使用新型细胞方法识别 B7 家族免疫检查点孤儿配体的受体

基本信息

批准号：
10058052
负责人：
Zhengyu Ma
金额：
$ 21.21万
依托单位：
ALFRED I. DU PONT HOSP FOR CHILDREN
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058052
关键词：
Affinity Antibodies Antigen-Presenting Cells Antigens Autoimmune Diseases Back Binding Biological Assay Blocking Antibodies CD276 gene CD3 Antigens CD58 gene Cell Line Cell physiology Cells Collection Custom Data Drug Targeting Enzyme-Linked Immunosorbent Assay Equilibrium Extracellular Domain Family Flow Cytometry Human IL4 gene Immune Targeting Immune response Immune system Immunologic Surveillance Individual Infection Integral Membrane Protein Interleukin-10 Lead Ligands Malignant Neoplasms Methods Modeling Monoclonal Antibodies Mus Nature Noise Normal tissue morphology Open Reading Frames Orphan Pathway interactions Patients Peptide/MHC Complex Pharmaceutical Preparations Play Production Protein Array Receptor Cell Receptor Gene Role Sensitivity and Specificity Signal Transduction Stains Streptavidin Surface Plasmon Resonance T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Th2 Cells Therapeutic VTCN1 gene base cDNA Library cancer cell chimeric antigen receptor immune checkpoint immune checkpoint blockade immune function mutant neoplastic cell novel prevent programmed cell death ligand 1 programmed cell death protein 1 receptor receptor binding response screening sensor tumor vector vector control

项目摘要

PROJECT SUMMARY/ABSTRACT T cells are central players in immune responses to infections and cancer. Once activated by antigens, T cells are able to directly kill infected cells and cancer cells, or direct other components of the immune system to attack targets. The awesome destructive power of T cells needs to be tightly controlled in order to avoid collateral damages to normal tissues and to prevent autoimmune diseases. An important mechanism of control is to inhibit T cell activities through B7 family immune checkpoint ligands. To date nine such ligands have been identified. They bind to receptors on T cells to inhibit T cell proliferation and activation. Interestingly, many types of tumor cells co-opt these ligands to evade T cell attack. Recently, antibodies that block the interactions between these ligands and their receptors have been developed to enhance immune response to cancer. These so-called immune checkpoint blockade drugs have been successful in controlling tumors in some patients, but the overall response rates are still low. One of the reasons may be that most of the drugs target the receptor of only one of the immune checkpoint ligands while cancer cells may express many of the different types of ligands. Currently, targeting additional receptors are difficult because the receptors for five of the ligands have yet to be identified. A major challenge for identifying their receptors is that they bind their ligands very weakly and currently available methods do not have enough sensitivity. To overcome this, we propose to develop a novel and highly sensitive cell-based approach to identify receptors for the five orphan ligands. The feasibility of the approach will be tested using model ligands and receptors that are known bind to each other. We will use the cell-based approach to screen transmembrane protein collections and the identified receptor candidates will be tested for their abilities to bind the orphan ligands. Receptors identified using our approach should help understand how B7 family immune checkpoint ligands control T cell responses and may serve as new targets for immune checkpoint blockade therapies against cancer.

项目摘要/摘要 T细胞是对感染和癌症免疫反应的核心参与者。一旦被抗原激活，T细胞能够直接杀死感染的细胞和癌细胞，或将免疫系统的其他成分引导到攻击目标。需要严格控制T细胞的令人敬畏的破坏力，以避免正常组织的附带损害并预防自身免疫性疾病。控制的重要机制是通过B7家族免疫检查点配体抑制T细胞活性。迄今为止九个这样的配体已经确定。它们与T细胞上的受体结合以抑制T细胞增殖和激活。有趣的是，很多肿瘤细胞的类型选择这些配体逃避T细胞攻击。最近，阻断相互作用的抗体这些配体之间的受体已经开发出来增强对癌症的免疫反应。这些所谓的免疫检查点封锁药物在某些人中已经成功地控制了肿瘤患者，但总体反应率仍然很低。原因之一可能是大多数药物的目标癌细胞的受体仅一个免疫检查点配体的受体可能表达许多不同的受体配体类型。目前，靶向其他受体很困难，因为五个受体配体尚未确定。识别其受体的主要挑战是它们约束配体非常弱，目前可用的方法没有足够的灵敏度。为了克服这一点，我们建议开发一种新型且高度敏感的基于细胞的方法，以鉴定五个孤儿配体的受体。这该方法的可行性将使用已知彼此结合的模型配体和受体进行测试。我们将使用基于细胞的方法来筛选跨膜蛋白收集和已识别的受体候选人的能力将被测试，以结合孤儿配体。使用我们的方法确定的受体应该有助于了解B7家族免疫检查点如何控制T细胞反应，并可以作为免疫检查点封锁疗法针对癌症的新靶标。