Novel mechanisms regulating PD-1 signaling and function

摘要 癌症免疫疗法代表了一种强大的、新出现的治疗范例，这两者都是因为它们的持久性 对多种肿瘤的临床反应和适用性。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)是一种关键的抑制因子 T细胞的检查点。恶性细胞的识别和清除可以通过阻断的抗体来实现 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，许多人经历了 与免疫相关的不良事件。新的研究表明，大约5-10%的患者表现出加速癌症。 在抗PD-1治疗后的进展，与基于当前机制模型的预测反应相反。两者都有 PD-1的潜在成功和失败是如此重要，理解PD-1信号显然是非常必要的 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 干扰配基结合。我们开发了一种分析质谱学数据的新方法，并发现 PD-1信号的新效应器。最令人兴奋的是，我们已经确定了多个候选基因，包括激酶VRK2，它 我们打算进一步调查。这项建议的首要目标是研究PD-1相关的激酶，以便 更好地定义新的信号通路并揭示导致PD-1耐药的T细胞内在机制 封锁。在第一个目标中，我们将发现VRK2控制T细胞中PD-1信号的分子机制。我们 我将进行结构-功能分析，以验证VRK2的S酶结构域是必需的 特异性PD-1功能，并利用生化和成像方法揭示VRK2的贡献 MAPK8IP1和MAP3K7与PD-1信号的相互作用。在第二个目标中，我们将检验VRK2的假设 是PD-1抑制体内细胞功能所必需的。我们将利用VRK2 KO小鼠通过以下方式揭示其机制 其中VRK2在PD-1阻断和耐药的背景下支持体内肿瘤的生长。鉴于PD的巨大影响- 1在公共卫生方面，拟议的工作意义非凡。

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.