Regulation of mRNA homeostasis by PD-L1

摘要 该项目的目标是确定免疫检查点程序性死亡的机制， 配体1（PD-L1）调节抗凋亡基因的mRNA稳态。作为细胞表面蛋白， PD-L1抑制T细胞反应，导致免疫逃逸。然而，PD-L1也具有重要的 非免疫细胞内的功能，这是少得多的理解。我们最近的研究表明IFNγ 诱导卵巢癌和前列腺癌细胞中PD-L1的核转位和积累。 此外，我们的初步数据表明，IFNγ诱导的PD-L1表达的抑制 增加细胞凋亡并降低NFκ B依赖性抗凋亡基因的mRNA水平。基于 基于这些发现，我们将检验核心假设，即细胞内PD-L1作为一种免疫调节剂， 抗凋亡基因mRNA稳态的调节剂。在目标1中，我们将确定PD-L1是否 通过促进抗凋亡基因的转录来增加它们的水平，和/或是否 增加卵巢癌和前列腺癌细胞中mRNA的稳定性。在目标2中，我们将确定 PD-L1是否直接结合抗凋亡基因启动子并促进其乙酰化， 我们将研究PD-L1是否结合抗凋亡mRNA并影响其亚细胞功能， 本地化虽然该项目的重点是NFκ B依赖的抗凋亡基因， 将可能揭示PD-L1调节其他细胞合成和/或稳定性的一般机制。 mRNA。靶向细胞表面PD-L1的免疫疗法已经显示出令人印象深刻的临床结果， 许多癌症;然而，只有一小部分患者获得持久的反应，突出了我们的 对PD-L1功能机制的不完全理解。这项研究的结果将 提供了关于PD-L1如何调节抗肿瘤细胞mRNA稳态的机制的第一个数据。 凋亡基因这一信息将促进我们对细胞内，免疫- PD-L1的独立功能，并可能导致靶向PD-L1的新疗法的开发。 L1在癌细胞中的抗凋亡功能。此外，该R16 SuRE项目将增强 研究环境在圣约翰大学提供学生从代表性不足 有许多机会学习生物医学研究的基础知识。

Abstract The goal of this project is to identify mechanisms by which immune checkpoint programmed death ligand 1 (PD-L1) regulates mRNA homeostasis of anti-apoptotic genes. As a cell surface protein, PD-L1 inhibits T cell responses, resulting in immune escape. However, PD-L1 also has important non-immune intracellular functions that are much less understood. Our recent studies show that IFNγ induces the nuclear translocation and accumulation of PD-L1 in ovarian and prostate cancer cells. In addition, our preliminary data indicate that suppression of the IFNγ-induced PD-L1 expression increases apoptosis and decreases mRNA levels of NFκB-dependent anti-apoptotic genes. Based on those findings, we will test the central hypothesis that the intracellular PD-L1 serves as a regulator of anti-apoptotic gene mRNA homeostasis. In Aim 1, we will determine whether PD-L1 increases the levels of anti-apoptotic genes by promoting their transcription, and/or whether it increases stability of their mRNAs in ovarian and prostate cancer cells. In Aim 2, we will determine whether PD-L1 directly binds to the anti-apoptotic gene promoters and facilitates their acetylation, and we will investigate whether PD-L1 binds the anti-apoptotic mRNAs and affects their subcellular localization. Although the project focuses on the NFκB-dependent anti-apoptotic genes, the results will likely reveal general mechanisms by which PD-L1 regulates synthesis and/or stability of other mRNAs. Immunotherapies targeting cell surface PD-L1 have shown impressive clinical outcomes in many cancers; however, only a fraction of patients achieves durable responses, highlighting our incomplete understanding of the mechanisms of PD-L1 functions. Findings from this study will provide the first data on the mechanisms of how PD-L1 regulates mRNA homeostasis of anti- apoptotic genes. This information will advance our understanding of the intracellular, immune- independent functions of PD-L1, and may lead to the development of novel therapies that target PD- L1 anti-apoptotic functions in cancer cells. In addition, this R16 SuRE project will enhance the research environment at St. John’s University by providing students from underrepresented backgrounds with numerous opportunities to learn the fundamentals of biomedical research.