Elucidation of Human Natural Killer Cell Development

人类自然杀伤细胞发育的阐明

• 批准号: 10587566
• 负责人: AHARON G FREUD
• 金额: $ 57.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587566
• 关键词: Acute Myelocytic Leukemia; Address; Award; Biological Assay; Blood; Bone Marrow; CD34 gene; Cancer Etiology; Cancer Model; Cancer Patient; Cell Differentiation process; Cell Lineage; Cell Separation; Cell physiology; Cells; Cessation of life; Clinical; Coculture Techniques; Complement; Data; Development; Developmental Cell Biology; Developmental Process; Effector Cell; Endometrial; Endometrial Carcinoma; Fetal Development; Fostering; Funding; Future; Genetic Transcription; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Hematopoietic stem cells; Human; Immune; Immune Targeting; Immune system; Immunity; Immunologic Surveillance; Immunosuppression; Immunotherapy; In Vitro; Innate Immune System; Institution; Invaded; Knowledge; Light; Lymphoid Cell; Lymphoid Tissue; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Measurement; Mediating; Methodology; Methods; Modeling; Molecular; Mus; Natural Immunity; Natural Killer Cells; Outcome; Pathway interactions; Peripheral; Phenotype; Physiological; Physiological Processes; Play; Pregnancy; Process; Production; Property; Public Health; Publishing; Regulation; Reporting; Role; Scientist; Series; Shapes; Signal Transduction; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Tonsil; Tumor Cell Invasion; Tumor Immunity; Tumor Promotion; Tumor-Derived; United States; Uterus; Woman; Work; angiogenesis; cancer cell; cancer immunotherapy; clinically relevant; cytotoxic; design; developmental plasticity; experimental study; fibrosarcoma; human tissue; improved; in vivo; lymph nodes; melanoma; mouse model; neoplastic cell; novel; permissiveness; precursor cell; prevent; prognostic; programs; stem; therapeutic target; therapy design; tumor; tumor growth; tumorigenic

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.

项目概要 该提案的重点是阐明调节人类自然杀伤 (NK) 细胞发育的过程 在健康状态和子宫内膜癌（EC）的情况下。 NK 细胞具有细胞毒性“1 组” 先天性淋巴细胞 (ILC) 在免疫中发挥着多种作用，对于控制恶性细胞至关重要 转变。 NK细胞在整个生命周期中在各种组织中经历终末分化和成熟 体，从而产生广泛的 NK 细胞表型和功能。所谓的传统 NK 细胞 (cNK) 产生于次级淋巴组织并在血液中占主导地位的细胞在以下方面发挥了作用： 补充 T 细胞介导的免疫监视。相比之下，专门的组织驻留 NK 细胞 (trNK) 它们的近亲 ILC1 在各种组织中发育并保留在那里以执行不同的功能。 在子宫中，trNK 细胞和 ILC1 的生理功能是通过以下方式支持和促进妊娠： 促进胎盘组织侵袭、免疫抑制和血管生成。我们假设在 EC 的设置子宫 trNK 细胞和 ILC1 发育和功能的正常过程是由 促进肿瘤细胞的生长和侵袭。我们在本提案中的目标是获得全面的 了解调节人类 NK 细胞健康发育的细胞和分子成分 组织并确定这些过程在 EC 环境中如何受到影响。我们的两个具体目标是：1) 定义人体组织中 NK 细胞和 ILC1 的发育途径； 2) 确定 NK 细胞如何 发育和功能由人类 EC 决定。特别是，在目标 1 中，我们将检验以下假设： NK 细胞和 ILC1 源自共同的第 1 组 ILC 前体细胞，我们最近在 人体淋巴组织。我们提出了一系列实验来检验我们的假设并确定 NK 细胞与源于新型前体细胞的 ILC1 发育轴的分子调节。 此外，我们将阐明健康人类子宫中 NK 细胞和 ILC1 的发育途径， 检验子宫 NK 细胞和 ILC1 也源自类似的第 1 组 ILC 前体细胞的假设，但 最终通过与淋巴组织不同的途径进行终末分化。在目标 2 中，我们将 检验以下假设：NK 细胞从常见的第 1 组 ILC 前体发育而来，偏向于 ILC1 和低细胞毒性子宫 trNK 细胞的产生，即使不促进肿瘤，也是允许的 生长。通过我们提出的研究，我们将确定 NK 细胞的发育、功能多样性和 可塑性由 EC 塑造。这些研究的临床重要性在于 EC 是最重要的 是美国常见的妇科恶性肿瘤，是癌症死亡的第六大原因 女性。此外，我们预测从我们的学习中获得的知识将提高我们的基础知识 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 针对先天免疫受到影响的 EC 和潜在其他形式的癌症的治疗。

项目成果

Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells.

• DOI: 10.3389/fimmu.2017.00360
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Scoville SD;Freud AG;Caligiuri MA
• 通讯作者: Caligiuri MA

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma.

高细胞毒性自然杀伤细胞与皮肤 T 细胞淋巴瘤患者的不良预后相关。

• DOI: 10.1182/bloodadvances.2018020388
• 发表时间: 2018
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Mundy-Bosse,Bethany;Denlinger,Nathan;McLaughlin,Eric;Chakravarti,Nitin;Hwang,Susan;Chen,Li;Mao,HsiaoyinCharlene;Kline,David;Youssef,Youssef;Kohnken,Rebecca;Lee,DeanAnthony;Lozanski,Gerard;Freud,AharonG;Porcu,Pierluigi;Willia
• 通讯作者: Willia