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

项目摘要： 免疫检查点受体如CTLA-4和PD-1已被成功靶向， 癌症免疫疗法我们早期的工作已经确定了V结构域免疫球蛋白抑制剂， T细胞活化（VISTA）作为一种免疫检查点蛋白，可关键调节抗肿瘤作用 免疫力尽管取得了这一进展，但VISTA如何抑制T细胞活化尚不清楚。我们 目前的研究已经鉴定了一种新的VISTA相互作用受体， 人T细胞中，并介导VISTA的抑制作用。本项目的总体目标是 建议是定义这种新的T细胞共抑制的细胞和分子机制， 复杂.具体目标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。目标2将审查 VISTA及其受体在调节肿瘤特异性T细胞应答中的作用，利用新的 产生了条件性基因敲除小鼠和阻断这种抑制性受体的新型抑制剂 复杂. VISTA及其受体在人癌组织中的蛋白质表达水平也将 接受检查。总之，这些拟议的研究将建立一个基础，开发新的 靶向VISTA受体复合物的抑制剂用于癌症免疫疗法。

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.