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)已成为当今时代的突破性治疗方法 癌症免疫疗法。然而，其中一个主要挑战是大多数患者都是这样做的 无反应，表明迫切需要确定和靶向非冗余免疫抑制 小路。在这方面，我们的初步研究发现了一种新的串扰机制 两种免疫检查点蛋白之间的相互作用，即免疫球蛋白抑制因子 细胞活化(Vista)和带有Ig和ITIM结构域的T细胞免疫受体(TIGIT)。我们 假设Vista和TIGIT形成一种新的共抑制受体复合体，可抑制T 激活细胞并导致T细胞功能障碍。这项提议将通过两个具体的 目标：首先，我们将进行诱变研究，并对这些突变体进行结合和 功能研究以更好地了解结合表位和结合之间的因果联系 和功能。最后，我们将研究Vista和TIGIT如何在 肿瘤以多克隆和抗原特异性的方式生长。总而言之，这些研究将 未来有必要研究开发阻断这种IC受体复合体的治疗性抑制剂， 逆转T细胞功能障碍，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.