Dissecting the roles of a novel immune-checkpoint receptor complex in driving T cell dysfunction in cancers

项目摘要。 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，最大的挑战之一是，大多数患者 没有反应，表明迫切需要确定和靶向非冗余免疫抑制剂 途径。在这方面，我们的初步研究已经确定了一种新的串扰机制 两种免疫检查点蛋白，即T- 细胞活化（VISTA）和具有IG和ITIM结构域的T细胞免疫受体（TIGIT）。我们 假设VISTA和TIGIT形成一种新共抑制受体复合物， 细胞激活并驱动T细胞功能障碍。该提案将通过两个具体的假设来检验这一假设。 目的：首先，我们将进行诱变研究，并将这些突变体进行结合， 功能研究，以更好地了解结合表位和结合之间的因果关系 和功能最后，我们将研究VISTA和TIGIT如何驱动T细胞功能障碍， 以多克隆和抗原特异性方式抑制肿瘤生长。这些研究将 保证未来的研究开发阻断这种IC受体复合物的治疗性抑制剂， 逆转T细胞功能障碍，并改善人类癌症的临床结果。

Project Summary. Immune checkpoint inhibitors (ICI) have become the breakthrough therapy in the era of cancer immunotherapy. However, one of the major challenges is that the majority of patients do not respond, indicating the urgent need to identify and target non-redundant immuno-suppressive pathways. In this regard, our preliminary studies have identified a novel cross talk mechanism between two immune checkpoint proteins, namely V-domain Immunoglobulin Suppressor of T- cell Activation (VISTA) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). We hypothesize that VISTA and TIGIT form a novel co-inhibitory receptor complex that dampens T cell activation and drives T cell dysfunction. This proposal will test this hypothesis by two specific aims: First, we will perform mutagenesis studies and subject these mutants to binding and functional studies to better understand the binding epitopes and the causal link between binding and function. Lastly, we will investigate how VISTA and TIGIT drive T cell dysfunction during tumor growth in both a polyclonal and antigen specific manner. Together, these studies will warrant future studies to develop therapeutic inhibitors that block this IC receptor complex, reverse T cell dysfunction, and improve clinical outcomes in human cancers.