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)调节抗细胞凋亡基因的mRNA动态平衡。作为一种细胞表面蛋白， 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 非免疫性细胞内功能，人们对此知之甚少。我们最近的研究表明，干扰素γ 诱导卵巢癌细胞和前列腺癌细胞中PD-L1的核转位和积聚。 此外，我们的初步数据表明，干扰素γ诱导的PD-L1表达受到抑制 增加细胞凋亡，降低依赖于核因子κB的抗凋亡基因的表达水平。基座 根据这些发现，我们将检验细胞内PD-L1作为一种 抗凋亡基因信使核糖核酸的动态平衡调节。在目标1中，我们将确定PD-L1 通过促进抗凋亡基因的转录来增加其水平，和/或 提高它们在卵巢和前列腺癌细胞中的mRNAs的稳定性。在目标2中，我们将确定 PD-L1是否直接与抗凋亡基因启动子结合并促进其乙酰化， 我们将研究PD-L1是否与抗凋亡的mRNAs结合并影响其亚细胞 本地化。尽管该项目关注的是依赖于核因子κB的抗凋亡基因，但结果 将可能揭示PD-L1调节其他受体合成和/或稳定性的一般机制 MRNAs。针对细胞表面PD-L1的免疫疗法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了持久的反应，这突显了我们的 对PD-L1功能机制的认识不全面。这项研究的发现将 为PD-L1调节抗癌基因mRNA动态平衡的机制提供了第一批数据 凋亡基因。这些信息将促进我们对细胞内、免疫- PD-L1的独立功能，并可能导致针对PD-L1的新疗法的开发。 L1在癌细胞中的抗凋亡功能。此外，这个R16 Sure项目将增强 圣约翰大学的研究环境，通过为代表不足的学生提供 有很多学习生物医学研究基础的机会的背景。

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.