Elucidation of Human Natural Killer Cell Development

项目总结 该提案侧重于阐明调节人类自然杀伤(NK)细胞发育的过程。 在健康状态下和在子宫内膜癌(EC)的背景下。NK细胞是细胞毒的“第一组” 先天淋巴样细胞(ILCs)在免疫中发挥着多种作用，对控制恶性肿瘤至关重要 转型。NK细胞在不同组织中经历了终末分化和成熟。 体内，导致了广泛的NK细胞表型和功能。所谓的常规自然杀伤细胞(CNK) 出现在次级淋巴组织中并在血液中占主导地位的已确立的作用 补充T细胞介导的免疫监视。相比之下，特化的组织驻留NK细胞(TrNK) 它们的近亲ILC1在各种组织中发育，并被保留在那里执行不同的功能。 在子宫中，trNK细胞和ILC1s在生理上被设计为通过以下方式支持和促进怀孕 促进胎盘组织侵袭、免疫抑制和血管生成。我们假设在 子宫trNK细胞的正常过程和ILC1的发育和功能由 促进肿瘤细胞的生长和侵袭。我们在这项提案中的目标是获得一个全面的 健康人群对调节人类NK细胞发育的细胞和分子成分的了解 并确定这些过程在EC环境中是如何受到影响的。我们的两个具体目标是：1) 确定人类组织中NK细胞和ILc1的发育途径；以及2)确定NK细胞如何 发展和功能是由人类的EC塑造的。特别是，在目标1中，我们将检验所有 NK细胞和ILC1s来源于共同的第1组ILC前体细胞，我们最近在 人类淋巴组织。我们提出了一系列实验来检验我们的假设，并确定 来自新的前体细胞的NK细胞与ILC1发育轴的分子调控。 进一步，我们将阐明NK细胞和ILC1s在健康人子宫中的发育途径， 验证子宫NK细胞和ILC1也来自相似的第1组ILC前体细胞的假设，但 最终通过不同于淋巴组织的途径进行终末分化。在《目标2》中我们将 检验一种假设，即共同的第1组ILC前体细胞的NK细胞发育偏向于 产生ILC1s和细胞毒性低的子宫trNK细胞，即使不促进肿瘤，也是允许的 成长。通过我们提议的研究，我们将确定NK细胞的发育、功能多样性和 可塑性是由EC塑造的。这些研究的临床意义在于EC是最重要的 美国常见的妇科恶性肿瘤，是#年癌症死亡的第六大原因 女人。此外，我们预计，从我们的学习中获得的知识将改善我们的基础 了解人类NK细胞发育生物学，并最终设计未来基于免疫的癌症 治疗EC和潜在的其他形式的癌症，在这些癌症中，天然免疫受到影响。

PROJECT SUMMARY This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development in the healthy state and in the setting of uterine endometrial carcinoma (EC). NK cells are cytotoxic “group 1” innate lymphoid cells (ILCs) that play myriad roles in immunity and are vital to controlling malignant transformation. NK cells undergo terminal differentiation and maturation in various tissues throughout the body, leading to a broad spectrum of NK cell phenotypes and functions. So-called conventional NK cells (cNK) that arise in secondary lymphoid tissues and predominate in the blood have established roles in complementing T cell-mediated immune surveillance. In contrast, specialized tissue-resident NK cells (trNK) and their close cousins, ILC1s, develop in various tissues and are retained there to carry out distinct functions. In the uterus, trNK cells and ILC1s are physiologically designed to support and promote pregnancy by promoting placental tissue invasion, immune suppression, and angiogenesis. We hypothesize that in the setting of EC the normal processes of uterine trNK cell and ILC1 development and function are co-opted by the tumor cells to promote their growth and invasion. Our goals in this proposal are to gain a comprehensive understanding of the cellular and molecular components that regulate human NK cell development in healthy tissues and to determine how these processes are impacted in the setting of EC. Our two specific aims are: 1) To define NK cell and ILC1 developmental pathways in human tissues; and 2) To determine how NK cell development and function are shaped by human EC. In particular, in Aim 1 we will test the hypothesis that all NK cells and ILC1s stem from a common group 1 ILC precursor cell, which we have recently identified in human lymphoid tissues. We propose a series of experiments to test our hypothesis and to determine the molecular regulation of the NK cell versus ILC1 developmental axis stemming from the novel precursor cell. Further, we will elucidate the developmental pathways of NK cells and ILC1s in the healthy human uterus, testing the hypothesis that uterine NK cells and ILC1s also stem from a similar group 1 ILC precursor cell but ultimately terminally differentiate through pathways distinct from those in lymphoid tissues. In Aim 2 we will test the hypothesis that NK cell development from the common group 1 ILC precursor is skewed towards the production of ILC1s and poorly cytotoxic uterine trNK cells that are permissive if not promoting of tumor growth. Through our proposed studies we will determine how NK cell development, functional diversity, and plasticity are shaped by EC. The clinical importance of these studies lies in the fact that EC is the most common gynecologic malignancy in the United States and is the sixth leading cause of cancer death in women. Further, we predict that the knowledge gained from our studies will improve our fundamental understand of human NK cell developmental biology and ultimately the design of future immune-based cancer therapies for EC and potentially other forms of cancer in which innate immunity is impacted.