Uncoupling pleiotropy in the LIGHT/HVEM/LTBetaR signaling network

项目摘要/摘要 免疫检查点的治疗调节已经成为一种变革性的新范式 癌症的治疗。这一进展引发了人们对瞄准新的协同调控途径的极大兴趣 以扩大免疫疗法的早期成功。这一努力中的一个主要挑战是广泛的 免疫信号通路的多效性。由于它们的配体：受体的混杂 在相互作用中，共调控蛋白可以产生多个、往往是相互矛盾的活动。这就带来了困难 正在开发的药物可以分离特定的通路功能，并模糊对 个体受体的生理学：配基对。LIGHT/HVEM/LTβR信令网是 这项挑战。光是一种免疫共刺激因子，在T细胞的激活和扩张中起着至关重要的作用 细胞。它通过疱疹病毒进入介体(Hvem)和淋巴毒素β受体发出信号。 (ltβR)，并被诱骗受体3(DcR3)拮抗。然而，这些受体中的每一个都结合了额外的 光以外的配体，导致了一个复杂和相互连接的信号网络。在此，我们建议 利用我们在结构引导蛋白质工程方面的专业知识来开发和表征光变体 可以解偶联LIGH/HVEM/LTβR通路的不同活性。我们要把这些“有偏见”的东西加进去 将等位基因导入转基因小鼠，以研究体内和平行的个体途径相互作用，我们将评估 免疫治疗模型中偏向光活动的治疗潜力。总而言之，这项提议将提供 深入了解关键的免疫调节途径、治疗开发的候选分子和新的 靶向多效性检查点受体的方法。

PROJECT SUMMARY/ABSTRACT Therapeutic modulation of immune checkpoints has emerged as a transformative new paradigm in the treatment of cancer. This development has triggered immense interest in targeting new co-regulatory pathways to amplify the early success of immunotherapy. A major challenge in this endeavor is the widespread pleiotropy characteristic to immune signaling pathways. Due to the promiscuity of their ligand:receptor interactions, co-regulatory proteins can produce multiple, often contradictory activities. This poses difficulty in developing agents that can isolate specific pathway functions and obscures a precise understanding of the physiology of individual receptor:ligand pairs. The LIGHT/HVEM/LTβR signaling network is a key exemplar of this challenge. LIGHT is an immune co-stimulator that plays a crucial role in the activation and expansion of T cells. It signals through both the Herpes virus entry mediator (HVEM) and the lymphotoxin beta receptor (LTβR), and it is antagonized by decoy receptor 3 (DcR3). However, each of these receptors binds additional ligands besides LIGHT, resulting in a complicated and interconnected signaling network. Here, we propose to leverage our expertise in structure-guided protein engineering to develop and characterize LIGHT variants that can uncouple the disparate activities of the LIGHT/HVEM/LTβR pathway. We will knock-in these “biased” alleles into transgenic mice to study individual pathway interactions in vivo and in parallel, we will assess the therapeutic potential of biasing LIGHT activity in models of immunotherapy. In sum, this proposal will provide insight into a pivotal immunoregulatory pathway, candidate molecules for therapeutic development, and new approaches for targeting pleiotropic checkpoint receptors.