Vista, A Novel Checkpoint that Suppresses Anti-Tumor T Cell Responses

Vista，一种抑制抗肿瘤 T 细胞反应的新型检查点

• 批准号: 10424513
• 负责人: Li Lily Wang
• 金额: $ 34.06万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424513
• 关键词: Binding; Biochemical; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell physiology; Clinical; Complex; Data; Development; Distal; Enzymes; Epitopes; Foundations; Functional disorder; Goals; Human; Immunofluorescence Immunologic; Immunoglobulin Domain; Impairment; Knockout Mice; Knowledge; Lead; Leucine-Rich Repeat; Ligands; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Mus; Mutagenesis; Outcome; Pathway interactions; Play; Proteins; Reagent; Receptor Activation; Regulatory T-Lymphocyte; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Tumor Immunity; Tumor-associated macrophages; Ubiquitin; Work; cancer immunotherapy; cancer therapy; checkpoint receptors; combinatorial; conditional knockout; immune checkpoint; inhibitor; leucine-rich repeat protein; malignant breast neoplasm; mutant; novel; programmed cell death protein 1; protein expression; receptor; recruit; small molecule; tumor

Project Summary: Immune-checkpoint receptors such as CTLA-4 and PD-1 have been successfully targeted for cancer immunotherapy. Our earlier work has identified V domain Immunoglobulin Suppressor of T cell Activation (VISTA) as an immune-checkpoint protein that critically regulates anti-tumor immunity. Despite this progress, how VISTA inhibits T cell activation is not understood. Our current study has identified a novel VISTA-interacting receptor that is expressed on murine and human T cells and mediates the suppressive effect of VISTA. The overarching goals of this proposal are to define the cellular and molecular mechanisms of this novel T cell coinhibitory complex. Specific aim 1 will dissect the interactions between VISTA and its receptor and establish the relevance of ubiquitin-modifying enzymes to the inhibitory signaling. Aim 2 will examine the role of VISTA and its receptor in regulating tumor-specific T cell responses, utilizing a newly generated conditional knockout mice and novel inhibitors that block this inhibitory receptor complex. The protein expression level of VISTA and its receptor in human cancer tissues will also be examined. Together, these proposed studies will build a foundation for developing novel inhibitors that target the VISTA receptor complex for cancer immunotherapy.

项目总结： CTLA-4和PD-1等免疫检查点受体已成功靶向于 癌症免疫疗法。我们早期的工作已经确定了V域免疫球蛋白抑制物 T细胞激活(VistA)作为一种免疫检查点蛋白对抗肿瘤起关键调节作用 豁免权。尽管取得了这一进展，但Vista是如何抑制T细胞激活的尚不清楚。我们的 目前的研究发现了一种新的Vista相互作用受体，该受体在小鼠和 并介导Vista的抑制作用。这个项目的首要目标是 建议确定这种新的T细胞共抑制的细胞和分子机制 很复杂。特殊目标1将剖析Vista与其受体之间的相互作用并建立 泛素修饰酶与抑制信号的相关性。Aim 2将研究 Vista及其受体在调节肿瘤特异性T细胞反应中的作用，利用一种新的 产生了条件性基因敲除小鼠和新型抑制剂来阻断这种抑制性受体 很复杂。VistA及其受体在人类癌症组织中的蛋白表达水平也将 接受检查。总之，这些建议的研究将为小说的发展奠定基础 针对Vista受体复合体的抑制剂，用于癌症免疫治疗。