Novel mechanisms regulating PD-1 signaling and function

摘要 癌症免疫疗法代表了一种强大的和新出现的治疗范式，这既是因为它们的持久性，也是因为它们的治疗效果。 临床反应和适用于各种肿瘤。免疫检查点疗法阻断抑制性受体 以增强抗肿瘤免疫反应。程序性细胞死亡蛋白1（PD-1）是一种重要的抑制性细胞凋亡的蛋白质。 T细胞的检查点恶性细胞的识别和清除可以通过抗体来实现， PD-1尽管这些抗体取得了成功，但大多数患者对PD-1阻断没有反应，许多患者在治疗过程中出现了严重的并发症。 免疫相关不良事件。新的研究表明，大约5-10%的患者表现出加速癌症， 与基于当前机制模型的预测应答相反，抗PD-1治疗后的进展。与两 PD-1的潜在成功和失败是如此重要，理解PD-1信号传导的需要显然是非常重要的。 迫切需要解释临床反应的机制，并开发超越简单的治疗方法， 干扰配体结合。我们开发了一种分析质谱数据的新方法， PD-1信号传导的新效应物。最令人兴奋的是，我们已经确定了多个候选者，包括激酶VRK 2， 我们打算进一步调查该提案的总体目标是研究PD-1相关激酶， 更好地定义新的信号通路，并揭示有助于PD-1抗性的T细胞内在机制 封锁在第一个目标中，我们将发现VRK 2控制T细胞中PD-1信号传导的分子机制。我们 将进行结构-功能分析，以检验VRK 2的酶结构域是介导 特定的PD-1功能，并利用生物化学和成像方法来揭示VRK 2的贡献 与MAPK 8IP 1和MAP 3 K7的相互作用朝向PD-1信号传导。在第二个目标中，我们将测试VRK 2 是体内PD-1抑制细胞功能所必需的。我们将利用VRK 2基因敲除小鼠来揭示其机制， 其中VRK 2在PD-1阻断和抗性的背景下支持体内肿瘤生长。鉴于PD的巨大影响- 1关于公共卫生，拟议的工作非常重要。

ABSTRACT Cancer immunotherapies represent a powerful and newly emergent therapeutic paradigm, both because of their durable clinical responses and applicability to a wide variety of tumors. Immune checkpoint therapies block inhibitory receptors on T cells in order to augment anti-tumor immune responses. Programmed cell death protein 1 (PD-1) is a critical inhibitory checkpoint for T cells. The identification and clearance of malignant cells can be brought about by antibodies which block PD-1. Despite the success of these antibodies, most patients do not respond to PD-1 blockade, and many experience immune-related adverse events. New studies indicate that some 5-10% of patients demonstrate accelerated cancer progression after anti-PD-1 treatment, in contrast to predicted responses based on current mechanistic models. With both the potential successes and failures of PD-1 being so significant, the need to understand PD-1 signaling is evidently very urgent, both for explaining the mechanism of clinical responses and for developing therapeutics that go beyond simply interfering with ligand binding. We have developed a new method to analyze mass spectrometry data and discovered novel effectors of PD-1 signaling. Most excitingly, we have identified multiple candidates, including the kinase VRK2 which we intend to investigate further. The overarching goal of this proposal is to study PD-1-associated kinases in order to better define novel signaling pathways and to uncover T cell-intrinsic mechanisms which contribute to resistance to PD-1 blockade. In the first aim, we will discover the molecular mechanism by which VRK2 controls PD-1 signaling in T cells. We will perform structure-function analyses to test the hypothesis that VRK2’s enzymatic domain is required for mediating specific PD-1 functions and utilize biochemical and imaging approaches to uncover the contribution made by VRK2 interactions with MAPK8IP1 and MAP3K7 towards PD-1 signaling. In the second aim we will test the hypothesis that VRK2 is required for PD-1 inhibition of cellular functions in vivo. We will utilize VRK2 KO mice to uncover the mechanism by which VRK2 supports tumor growth in vivo in the context of PD-1 blockade and resistance. Given the large impact of PD- 1 on public health, the proposed work is incredibly significant.