PAG is a novel target in immunotherapy

项目摘要 免疫检查点疗法阻断T细胞上的抑制性受体以增强抗肿瘤免疫应答。 程序性细胞死亡-1（PD-1）途径是T细胞和抗体的关键抑制性检查点。 阻断PD-1可促进免疫介导的恶性细胞识别和清除。癌 免疫疗法，包括抗PD-1抗体，代表了强大的治疗范例，因为它们 适用于多种肿瘤，并可产生持久的临床反应。不幸的是，只有一个 部分患者证实了当前药物的临床获益。因此，迫切需要 开发更有效地靶向PD-1信号传导以及其他检查点抑制剂的治疗方法。我们 已经采用磷酸蛋白质组学方案来鉴定调节PD-1下游信号传导的蛋白质。 通过这种方法，我们将蛋白PAG鉴定为PD-1免疫检查点信号传导的效应物。我们 已经发现PAG是PD-1信号传导和抑制T细胞功能所必需的，我们的初步研究表明， 遗传和生物化学研究证实PAG是逆转T细胞抑制的靶点。这一近期目标 该提议是为了验证PAG作为检查点抑制剂候选物。我们的长期目标是将我们的 研究结果，并为恶性肿瘤患者产生新的免疫疗法。我们将实现这些目标 目标如下：目标1。定义PD-1诱导PAG磷酸化以 促进免疫检查点激活。使用高分辨率显微镜，我们将确定PD-1和 PAG聚集在免疫突触上。使用诱变，我们将定义特定的 PAG的胞质区域内的酪氨酸用于PD-1功能和免疫突触聚集。目标二。到 在体内评估PAG介导的免疫抑制潜力。我们将在同基因模型中评估肿瘤生长 使用PAG敲除小鼠。目标3。研制抗PAG功能性抗体。我们将制定战略， 体内靶向PAG。总之，这些研究将揭示PAG介导抑制性细胞凋亡的机制。 T细胞中的信号及其作为免疫检查点阻断的新靶点的价值。

PROJECT ABSTRACT Immune checkpoint therapies block inhibitory receptors on T cells to augment anti-tumor immune responses. The Programmed cell Death-1 (PD-1) pathway is a critical inhibitory checkpoint for T cells, and antibodies blocking PD-1 promote immune-mediated identification and clearance of malignant cells. Cancer immunotherapies, including anti-PD-1 antibodies, represent a powerful therapeutic paradigm because they are applicable to a wide variety of tumors and can produce durable clinical responses. Unfortunately, only a fraction of patients demonstrates clinical benefit from current agents. As such, there is an urgent need to develop therapeutics that more effectively target PD-1 signaling as well as other checkpoint inhibitors. We have employed phosphoproteomic protocol to identify proteins that regulate downstream signaling of PD-1. With this approach, we identified the protein PAG as an effector of PD-1 immune checkpoint signaling. We have discovered that PAG is required for PD-1 signaling and inhibition of T cell function and our preliminary genetic and biochemical studies confirm PAG as a target for reversing T cell inhibition. The immediate goal of this proposal is to validate PAG as checkpoint inhibitor candidate. Our long-term goal is to translate our findings and to generate novel immunotherapies for patients with malignancies. We will accomplish these goals with the following aims: Aim 1. Define the mechanism by which PD-1 induces PAG phosphorylation to promote immune checkpoint activation. Using high resolution microscopy, we will determine how PD-1 and PAG cluster at the immunological synapse. Using mutagenesis, we will define the requirement for specific tyrosine within the cytoplasmic region of PAG for PD-1 function and immune synapse clustering. Aim 2. To assess PAG-mediated immune inhibitory potential, in vivo. We will assess tumor growth in syngeneic models using PAG knockout mice. Aim 3. To develop anti-PAG functional antibodies. We will develop strategies to target PAG in vivo. Together, these studies will uncover the mechanism by which PAG mediates inhibitory signals in T cells and its value as a novel target for immune checkpoint blockade.