Uncoupling pleiotropy in the LIGHT/HVEM/LTBetaR signaling network

项目总结/摘要 免疫检查点的治疗性调节已经成为免疫学领域的变革性新范式。 癌症的治疗。这一发展引发了人们对新的协同调控途径的极大兴趣 扩大免疫疗法的早期成功。这一奋进的一个主要挑战是， 免疫信号传导通路的多效性特征。由于其配体的混杂性：受体 在相互作用中，共调节蛋白可以产生多种通常相互矛盾的活性。这就造成了困难， 开发可以分离特定途径功能并模糊对这些功能的精确理解的试剂。 单个受体：配体对的生理学。LIGHT/HVEM/LTβR信号网络是一个关键的范例， 这个挑战。LIGHT是一种免疫共刺激因子，在T细胞的激活和扩增中起着至关重要的作用。 细胞它通过疱疹病毒进入介质（HVEM）和光敏素β受体发出信号 (LTβR），并被诱饵受体3（DcR 3）拮抗。然而，这些受体中的每一种都结合额外的 配体，导致一个复杂的和互连的信号网络。在此，我们建议 利用我们在结构导向蛋白质工程方面的专业知识，开发和表征LIGHT变体， 可以解偶联LIGHT/HVEM/LTβR通路的不同活性。我们会把这些“有偏见的” 将等位基因植入转基因小鼠中以研究体内和平行的个体途径相互作用，我们将评估 在免疫治疗模型中偏置LIGHT活性的治疗潜力。总而言之，这项建议将提供 深入了解一个关键的免疫调节途径，用于治疗开发的候选分子， 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.