The Roles of a Novel Immune-Checkpoint Receptor Complex in Driving T Cell Dysfunction in Cancer

新型免疫检查点受体复合物在驱动癌症 T 细胞功能障碍中的作用

• 批准号: 10569043
• 负责人: Li Lily Wang
• 金额: $ 22.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569043
• 关键词: Address; Antigen-Presenting Cells; Automobile Driving; Binding; Binding Proteins; Biological Assay; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Lineage; Clinical; Complement; Complex; Environment; Functional disorder; Future; Gene Expression Profile; Genes; Human; ITIM; Immune; Immune checkpoint inhibitor; Immunoglobulin Domain; Impairment; Individual; Knockout Mice; Laboratories; Ligands; Malignant Neoplasms; Mediating; Modeling; Mutagenesis; Myelogenous; Myeloid Cells; Natural Killer Cells; Outcome; P-selectin ligand protein; Pathway interactions; Patients; Phenotype; Physiological; Proteins; Receptor Signaling; Role; Signal Transduction; Suppressor-Effector T-Lymphocytes; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissue-Specific Gene Expression; Tumor Antigens; Tumor Immunity; anti-tumor immune response; cancer immunotherapy; checkpoint receptors; exhaustion; immune checkpoint; improved; inhibitor; inhibitor therapy; melanoma; mouse model; mutant; neoplastic cell; novel; receptor; receptor binding; response; transcriptome; transcriptomics; tumor

Summary Immune checkpoint inhibitors (ICI) have become the breakthrough therapy in the era of cancer immunotherapy. However, one of the major challenges is that majority of patients do not respond, indicating the urgent need to identify and target non-redundant immunosuppressive pathways. Our preliminary studies have identified a novel cross-talk mechanism between two immune checkpoint receptors. We hypothesize that this novel cross-talk mechanism drives T cell exhaustion and impair anti-tumor immune response. We will test this hypothesis by two specific aims: in Aim 1, we will determine the causal relationship between receptor binding and the inhibitory effects on T cell activation. In Aim 2, we will investigate how this novel cross-talk mechanism drives T cell exhaustion and whether blocking this axis can enhance T cell-mediated anti-tumor immunity. Together, these studies will guide future studies to target this novel axis, reverse T cell exhaustion, and improve clinical outcomes in cancer patients.

总结 免疫检查点抑制剂（ICI）已成为免疫检查点时代的突破性疗法。 癌症免疫疗法然而，一个主要的挑战是，大多数患者不 反应，表明迫切需要确定和靶向非冗余免疫抑制剂 途径。我们的初步研究已经确定了一种新的串扰机制， 免疫检查点受体。我们假设这种新的串扰机制驱动T细胞 疲劳和抗肿瘤免疫应答受损。我们将通过两个具体的实验来验证这一假设。 目的：在目的1中，我们将确定受体结合与受体结合之间的因果关系。 对T细胞活化的抑制作用。在目标2中，我们将研究这种新颖的串扰如何 机制驱动T细胞耗竭，阻断这一轴是否可以增强T细胞介导的免疫功能， 抗肿瘤免疫总之，这些研究将指导未来的研究，以针对这一新的轴， 逆转T细胞耗竭，改善癌症患者的临床结果。