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.

项目摘要 该提案的重点是阐明治理人类自然杀手（NK）细胞开发的过程 在健康状态和子宫子宫内膜癌（EC）的情况下。 NK细胞是细胞毒性的“第1组” 在免疫中起无数角色的先天淋巴样细胞（ILC），对控制恶性至关重要 转型。 NK细胞在整个整个时机中都经历末端分化和成熟 身体，导致广泛的NK细胞表型和功能。所谓的常规NK细胞（CNK） 这是在次级淋巴组织中出现的，在血液中占主导 补充T细胞介导的免疫监测。相反，专门的组织居民NK细胞（TRNK） 他们的近乎表亲ILC1在各种时机中发展，并保留在那里以执行不同的功能。 在子宫中，TRNK细胞和ILC1的物理设计旨在支持和促进通过 促进位置组织侵袭，免疫抑制和血管生成。我们假设在 EC设置子宫TRNK细胞和ILC1发育和功能的正常过程由 肿瘤细胞促进其生长和侵袭。我们在此提案中的目标是获得全面的 了解调节人类NK细胞在健康中的细胞和分子成分 组织并确定在EC的情况下如何影响这些过程。我们的两个具体目标是：1） 定义人体组织中的NK细胞和ILC1发育途径； 2）确定NK细胞如何 发展和功能由人类EC塑造。特别是，在AIM 1中，我们将检验以下假设 NK细胞和ILC1S源自一个共同的1组ILC前体细胞，我们最近在该细胞中鉴定出来 人淋巴组织。我们提出了一系列实验，以检验我们的假设并确定 NK细胞与ILC1发育轴的分子调节来自新的前体细胞。 此外，我们将阐明健康人子宫中NK细胞和ILC1的发育途径， 检验子宫NK细胞和ILC1也源于类似的1组ILC前体细胞，但 最终通过与淋巴组织中不同的途径分化。在目标2中，我们将 检验以下假设：公共组1 ILC前体的NK细胞发育偏向于 生产ILC1和细胞毒性子宫TRNK细胞，如果不促进肿瘤 生长。通过我们提出的研究，我们将确定NK细胞的发展，功能多样性和如何 可塑性是由EC塑造的。这些研究的临床重要性在于EC是最多的事实 美国常见的妇科恶性肿瘤，是癌症死亡的第六个主要原因 女性。此外，我们预测从我们的研究中获得的知识将改善我们的基本 了解人类NK细胞发育生物学，并最终设计未来的免疫癌症 EC的疗法以及可能影响先天免疫力的其他形式的癌症。

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